ArticlePDF AvailableLiterature Review

Abstract and Figures

Andrographolide, a diterpenoid, is known for its anti-inflammatory effects. It can be isolated from various plants of the genus Andrographis, commonly known as ‘creat’. This purified compound has been tested for its anti-inflammatory effects in various stressful conditions, such as ischemia, pyrogenesis, arthritis, hepatic or neural toxicity, carcinoma, and oxidative stress, Apart from its anti-inflammatory effects, andrographolide also exhibits immunomodulatory effects by effectively enhancing cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). All these properties of andrographolide form the foundation for the use of this miraculous compound to restrain virus replication and virus-induced pathogenesis. The present article covers antiviral properties of andrographolide in variety of viral infections, with the hope of developing of a new highly potent antiviral drug with multiple effects.
This content is subject to copyright. Terms and conditions apply.
1 23
Archives of Virology
Official Journal of the Virology
Division of the International Union of
Microbiological Societies
ISSN 0304-8608
Arch Virol
DOI 10.1007/s00705-016-3166-3
Broad-spectrum antiviral properties of
andrographolide
Swati Gupta, K.P.Mishra & Lilly Ganju
1 23
Your article is protected by copyright and
all rights are held exclusively by Springer-
Verlag Wien. This e-offprint is for personal
use only and shall not be self-archived
in electronic repositories. If you wish to
self-archive your article, please use the
accepted manuscript version for posting on
your own website. You may further deposit
the accepted manuscript version in any
repository, provided it is only made publicly
available 12 months after official publication
or later and provided acknowledgement is
given to the original source of publication
and a link is inserted to the published article
on Springer's website. The link must be
accompanied by the following text: "The final
publication is available at link.springer.com”.
REVIEW
Broad-spectrum antiviral properties of andrographolide
Swati Gupta
1
K. P. Mishra
1
Lilly Ganju
1
Received: 6 June 2016 / Accepted: 20 October 2016
ÓSpringer-Verlag Wien 2016
Abstract Andrographolide, a diterpenoid, is known for its
anti-inflammatory effects. It can be isolated from various
plants of the genus Andrographis, commonly known as
‘creat’. This purified compound has been tested for its anti-
inflammatory effects in various stressful conditions, such
as ischemia, pyrogenesis, arthritis, hepatic or neural toxi-
city, carcinoma, and oxidative stress, Apart from its anti-
inflammatory effects, andrographolide also exhibits
immunomodulatory effects by effectively enhancing cyto-
toxic T cells, natural killer (NK) cells, phagocytosis, and
antibody-dependent cell-mediated cytotoxicity (ADCC).
All these properties of andrographolide form the founda-
tion for the use of this miraculous compound to restrain
virus replication and virus-induced pathogenesis. The
present article covers antiviral properties of andro-
grapholide in variety of viral infections, with the hope of
developing of a new highly potent antiviral drug with
multiple effects.
Abbreviations
NK cells Natural killer cells
T
regs
Regulatory T cells
CTLs Cytotoxic T lymphocytes
IAV Influenza A virus
NS Non-structural
HBV Hepatitis B virus
NC Nucleocapsid
DCs Dendritic cells
HCV Hepatitis C virus
HSV Herpes simplex virus
EBV Epstein-Barr virus
HPV Human papillomavirus
HIV Human immunodeficiency virus
AIDS Acquired immunodeficiency syndrome
gp Glycoprotein
CNS Central nervous system
CHIKV Chikungunya virus
NCR Non-coding region
HBsAg Hepatitis B surface antigen
HBeAg Hepatitis B envelope antigen
14-DDA 14-Deoxy-11,12-didehydroandrographolide
DAD 14-Deoxyandrographolide
IPAD 3, 19-Isopropylideneandrographolide
ACV Acyclovir
HSV-1DR HSV-1 drug-resistant strain
CPE Cytopathic effect
RIG-1 Retinoic acid inducible gene 1
RLRs RIG-1-like receptors
HO-1 Haeme oxygenase 1
DASM Dehydroandrographolide succinic acid
monoester
BAL Bronchoalveolar
ADCC Antibody-dependent cell-mediated
cytotoxicity
Introduction
Viruses are infectious agents that infect host cells to
increase their progeny. In some cases, viral infection
results in lysis of the host cell leading to the release of
millions of copies of the virus. Viruses exploit the host cell
&K. P. Mishra
kpmpgi@rediffmail.com
1
Immunomodulation Laboratory, Defence Institute of
Physiology and Allied Sciences, Lucknow Road, Timarpur,
Delhi 110054, India
123
Arch Virol
DOI 10.1007/s00705-016-3166-3
Author's personal copy
by using their replication machinery and also affect the
energy balance required for the survival of the cell.
Imbalanced energy production and energy expenditure
results in apoptosis. Some viruses not only survive by
successfully evading the host immune system but are also
able to suppress it, causing various detrimental infectious
and opportunistic diseases. Chronic infection can cause
altered expression of housekeeping genes and proteins of
the cell, thus transforming it into a cancerous cell or
hyperactivating the immune system, thereby initiating the
destruction of host cells in order to kill virus-infected cells.
This state of activation triggers an autoimmune response
leading to destruction of host cells.
Some antiviral drugs stimulate the host immune system
to attack the virus, providing protection against a variety of
viral infections. These drugs are considered better than
virus-specific antiviral drugs, which act on entry, release,
replication, integration or other stages of the virus life
cycle. Their nonspecific mechanism of action can kill other
microorganisms and parasites, which is another advantage
of using immune-stimulating antiviral drugs.
Andrographolide is a drug that has antiviral (Table 1)
[1], antimicrobial [24] and anti-parasitic effects [57]. It
is a labdane diterpenoid (Fig. 1) that can be purified from
the aerial parts of various plants of the genus Andrographis
(family Acanthaceae), which grow at different elevations.
The bitter taste of the bioactive component of Andro-
graphis paniculata gave this plant the title of ‘‘King of
Bitter’’. A. paniculata is found in India, Sri Lanka, China,
Malaysia, Thailand, and Japan at an elevation of up to
1000 m [8]. It is an annual herb about 30-110 cm tall, with
white flowers with purple spots on the petals. Andro-
grapholide is soluble in organic solvents such as ethanol,
chloroform, ether, acetone, and dimethyl sulfoxide, and can
be extracted from A. paniculata,A. alata, and A. lineate
[9].
The anti-inflammatory effects of andrographolide can
efficiently neutralize cell-lysis-induced inflammation.
Andrographolide-mediated suppression of NF-jB and NO
contributes to its anti-inflammatory properties [1013]. The
differential apoptosis of cancer cells can be induced by
andrographolide, which can inhibit virus-induced carcino-
genesis. Its pro-apoptotic role in hamster buccal pouch
carcinoma and human colorectal carcinoma has been
reported by Shanmugam et al. and Lin et al., respectively
[14,15]. Andrographolide induced apoptosis in human
cancer cell line [16] by activation of caspase 8, caspase-8-
dependent cleavage of Bid, and conformational changes in
Bax has been demonstrated by Zhou et al. [17]. Mito-
chondria-mediated apoptosis in lymphoma cells induced by
andrographolide has been reported by Yang et al. [18].
Further inhibitory effects of andrographolide on migration,
invasion and matrix metalloproteinase expression has also
been described in rheumatoid arthritis, angiogenesis, breast
cancer, human colorectal carcinoma and human small-cell
lung carcinoma [1923]. In contrast to the role of andro-
grapholide as a pro-apoptotic agent, it can induce prolif-
eration of cytotoxic T lymphocytes (CTLs) both in vitro
and in vivo [24], which can kill virus-infected host cells.
Andrographolide plays a role in mitigation of autoimmune
responses. Iruretagoyena et al. reported the reduction of
experimental autoimmune encephalomyelitis by interfering
with T-cell activation [25]. Andrographolide also possesses
cytoprotective properties against various oxidative stresses.
It has a neuroprotective effect in permanently cerebral
ischaemic rats [26] and against nicotine–induced oxidative
stress in the brains of male Wistar rats [27]. It also has
hepatoprotective properties against carbon-tetrachloride-
induced oxidative damage in rats [28], ethanol-induced
hepatorenal toxicity in mice [29], and concanavalin-A-in-
duced liver injury [30]. Therefore, andrographolide
nanoparticles have also been engineered to aid in rapid
recovery from liver toxicity [31].
Andrographolide also modulates the host immune
response. Injection of killed Salmonella vaccine in mice
and subsequently feeding them with different quantities of
andrographolide resulted in a significant increase of S.
typhimurium-specific IgG antibodies [32]. Cyclophos-
phamide-induced delayed-type hypersensitivity was
reversed by a mixture of various purified labdane diterpe-
nes of A. paniculata [33]. Andrographolide also reduces
IL-2 production in T cells by interfering with nuclear factor
of activated T cells (NFAT) activation and ERK-1 and
ERK-5 phosphorylation [34]. Sheeja et al. reported that
CTL and NK cell activity were upregulated by andro-
grapholide treatment [35]. Peng et al. observed an increase
in phagocytic activity along with induction of the cytokines
IFN-a, IFN-c, and TNF-ain peripheral blood mononuclear
cells (PBMCs) [36].
The properties of andrographolide, such as its ability to
induce apoptosis of cancer cells and inhibition of DTH, its
anti-oxidative and cytoprotective effect, and its ability to
enhance CTLs and NK cell activation makes it a potent
antiviral agent. In the present review, we discuss the broad-
spectrum antiviral properties of andrographolide against
different viruses, which are summarized in Figure 2.
Influenza A virus (IAV)
Influenza A virus (IAV) is a negative-sense, single-strand
RNA virus belonging to the family Orthomyxoviridae and
genus Influenzavirus A. It is a spherical virus that is
80-120 nm in diameter with an external layer of spike-like
projections. IAV is a causative agent of respiratory infec-
tion in humans, and virus replication takes place in
epithelial cells of the upper and lower respiratory tract.
S. Gupta et al.
123
Author's personal copy
Table 1 Antiviral effects of andrographolide on different viruses
Virus Genome type Cells affected Associated complications in humans In vivo or
in vitro studies
Dose of
andrographolide
used
Effect of andrographolide Ref.
Influenza A virus Negative-
sense
single-
stranded
RNA
Epithelial cells of the
upper and lower
respiratory tract
Respiratory infection including
pneumonia, sinus infections, asthma,
etc.
BALB/c mice
and MDCK
cells
4000 to 125 mg/
kg/d
1. Inhibits H9N2, H5N1 and H1N1
virus both in vitro and in vivo
[41]
DCs and
macrophages
250 lg/ml 2. Inhibits the H1N1-induced RIG-1-
like receptor signaling pathway
[44]
MDCK cells 200 to 3277.4
lg/ml
3. Inhibits H3N2 virus replication [45]
Hepatitis B virus Partially
double-
stranded
relaxed
circular
DNA
Hepatocytes, DCs,
T
regs
and NK cells
Liver cirrhosis, fibrosis and hepatocellular
carcinomas
HepG 2.2.15
cells
54.1 to 200 lM Inhibits HBV DNA replication [55]
Hepatitis C virus Positive-sense
single-
stranded
RNA
Hepatocytes, PBMCs,
especially B cells
Chronic hepatitis, liver cirrhosis, and
hepatocellular carcinoma and
extrahepatic infection, resulting in B cell
non-Hodgkin’s lymphoma
Huh 7 cells 1 to 10 lM Suppresses HCV genome replication
by promoting IFNaresponse, viral
HO-1 gene activity and inhibiting
viral NS3/4A protease activity
[60]
Molecular
docking
study
- Inhibits HCV NS3/4A protease and
its drug-resistant mutants
[61]
Herpes simplex virus
1
Double-
stranded
DNA virus
Skin and mucosal
epithelial cells
Blister formation at skin and mucosal
membrane of mouth, lips, genitals and
oesophagus and conjunctivitis, keratitis,
iridocyclitis and acute retinal necrosis in
the ocular region
Vero cells 8- 89 lg/ml 1. Reduces HSV-1-induced plaque
formation
2. Inhibits HSV-1 DNA replication
and gp C and D expression
[66]
Vero cells 16.28 -76.3 lM Inhibits HSV-1 entry into the cell [67]
Vero cells 20.50 lM Andrographolide analogue, 3,
19-isopropylideneandrographolide
inhibits HSV-1 wild-type and drug
resistant strains’ DNA and protein
synthesis
[68]
Epstein-Barr virus Linear
double-
stranded
DNA virus
B cells and epithelial
cells of salivary
gland and also T
cells, NK cells and
smooth muscle cells
Nasopharyngeal carcinoma, Burkitt’s
Lymphoma, Hodgkin’s Lymphoma,
gastric carcinoma, multiple sclerosis and
lymphomatoid granulomatosis
P3HR1 cells 1- 10 lg/ml Inhibits two viral immediate early
genes, resulting in inhibition of
viral lytic protein expression
[73]
Human
papillomavirus
Double-
stranded
circular
DNA
Basal epithelial cells Genital warts and cancer in cervical,
vulvar, vaginal, penile, anal, and
oropharyngeal region
CaSki cells 9- 152.34 lM Inhibits E6 oncogenic envelope gp
and restores tumor suppressor p53
protein
[76]
Andrographolide as an antiviral agent
123
Author's personal copy
Patients with IAV release aerosol particles containing the
virus into the environment, which leads to the spread of the
virus to a new host [37]. IAV infects variety of animals,
including waterfowl as their original reservoir, whales,
seals, cats, dogs, swine, poultry, and humans. The genome
of IAVs consists of eight segments [38]. Segment 1-6 of
the IAV genome code for single proteins, i.e., polymerase
PB2, polymerase PB1, polymerase PA, haemagglutinin
(HA), nucleoprotein and neuraminidase (NA), respec-
tively. Segments 7 and 8 have overlapping reading frames
encoding matrix proteins (MI and M2) and nonstructural
(NS) proteins (NS1 and NS2), respectively. IAV has two
surface glycoproteins (gp), namely HA, a trimer consisting
of three identical subunits, and NA, a tetrameric spike [39].
HA binds to a sialic acid receptor to allow infection of the
host, whereas NA cleaves the receptor to allow the release
of the virus. Human bronchoalveolar (BAL) fluid exhibits
innate immune defense activity against influenza virus.
Resistance to BAL fluid of a drug-resistant H1N1 virus due
to its NA gene activity has been shown to result in
increased viral fitness [40]. Therefore, more-efficient
antiviral drugs are required to inhibit viral gene activity,
which should slow down the evolution of drug-resistant
forms.
Andrographolide has been proposed to be a very
effective drug against IAV. Chen et al. showed that
andrographolide and its various derivatives inhibit H9N2,
H5N1 and H1N1 strains of influenza virus, both in vitro
and in vivo [41]. Andrographolide has also been screened
using the Lipinski rule, which evaluates if compounds with
biological activity can be used as drugs in humans. Raja
et al. screened andrographolide using the Lipinski rule and
found that andrographolide, with a molecular weight
Fig. 1 Structure of andrographolide
Table 1 continued
Virus Genome type Cells affected Associated complications in humans In vivo or
in vitro studies
Dose of
andrographolide
used
Effect of andrographolide Ref.
Human
immunodeficiency
virus
Two identical
copies of
single-
stranded
positive-
sense RNA
Macrophages,
monocytes, DCs and
microglial cells and
CD4
?
T cells
AIDS and opportunistic infections H9 cells 50- 200 lg/ml 1. Increases CD4
?
T cell count [79]
MT2 cells 5 to 100 mg/mL 2. Reduces p24 antigen levels [80]
Chikungunya virus Single-
stranded
positive-
sense RNA
Epithelial, endothelial,
fibroblasts,
monocytes and
macrophage cells
Fever, headache, rashes, myalgia, and
polyarthralgia
HepG2 cells 1 to 100 lM Reduces viral RNA copy number
and inhibits viral protein
expression
[83]
S. Gupta et al.
123
Author's personal copy
350.455 (must be B500) has three hydrogen bond donors
(must be B5) and five hydrogen bond acceptors (must be
B10). In addition, a molecular docking study revealed that
andrographolide forms five hydrogen bonds with HA and
three H bonds with NA with binding energy values of -6.48
and -7.04 kcal/mol, respectively, signifying the interaction
of andrographolide with virus proteins in regulating various
biological processes [42]. Host innate immune factors such
as retinoic acid inducible gene-1 (RIG-1)-like receptors
(RLRs) are involved in detection of RNA viruses inside the
cytoplasm. The RLR family includes RIG-1, MDA5, and
LGP2, which, on sensing RNA viruses, induce the initia-
tion and modulation of antiviral immunity of the host [43].
Infection with H1N1 leads to the activation of the RLR-
dependent signaling pathway. Andrographolide inhibits the
H1N1-induced RIG-1-like receptor signaling pathway in
human bronchial epithelial cells, indicating inhibition of
virus-induced activation of the RLR pathway, leading to
amelioration of H1N1-virus-induced cell mortality [44].
Yuan et al synthesized 18 new semi-synthetic andro-
grapholide analogues and bio-assayed their anti-influenza
A virus (H3N2) activity in vitro. Among the compounds
synthesized, benzyl amino derivative 38 showed the
highest potency and was 1.5 times more efficient than
lianbizhi, an andrographolide analogue used in Chinese
medicines [45]. Moreover, the effectiveness of A. panicu-
lata extract SHA-10 on patients suffering from the com-
mon cold was evaluated by Caceres et al. by visual
analogue scale measurement [46]. Their study concluded
that SHA-10 dried extract (1200 mg/day) effectively
reduced the prevalence and intensity of uncomplicated
common cold symptoms at day two of treatment.
Hepatitis B virus
Hepatitis B virus (HBV), a DNA virus, belongs to the
family Hepadnaviridae and genus Orthohepadnavirus.
Hepatitis B is an infectious disease caused by HBV
infection, which affects hepatocytes, leading to cirrhosis,
fibrosis and hepatocellular carcinomas. HBV is about
42 nm in diameter, consisting of an outer lipoprotein coat
and the hepatitis B surface antigen (HBsAg). The HBV
genome is 3.2 kb long and is a partially double-stranded,
relaxed circular DNA packaged in a nucleocapsid (NC).
HBsAg can either exist as viral-particle-bound protein or as
a free noninfectious protein. In utero viral exposure to fetal
Fig. 2 Effects of
andrographolide on the immune
system and virus entry and
propagation
Andrographolide as an antiviral agent
123
Author's personal copy
immune cells results in a symbiotic relationship between
HBV and its host, which might have lead to the wide
distribution of HBV to large part of the human population
[47]. Vaccines against HBV contain HBsAg to generate
neutralizing antibodies providing long-term protection
[48].
The transmission of HBV mostly takes place percuta-
neously, sexually, perinatally and through blood transfu-
sion, but patterns of HBV transmission vary throughout the
world. HBV can infect humans and non-human primates of
the families Hominidae (chimpanzees, gorillas, and oran-
gutans) and Hylobatidae (gibbons) [49]. HBV infection
activates CD4 and CD8 T-cell and B-cell responses.
However, the presence of immunosuppressive regulatory T
cells (T
regs
) contributes to an inadequate immune response
against HBV, causing a chronic infection [50]. The
immune cells and pathways targeted by HBV include
dendritic cells (DCs), T
regs
, NK cells, and the interferon
(IFN) pathway, respectively [51].
A number of chemical or plant-derived compounds have
been screened and approved for HBV treatment [52,53].
The side effects of the currently approved drugs and
resistance developed by the virus has forced a further
search for anti-HBV agents [54]. Chen et al. synthesized 48
derivatives of dehydroandrographolide and andro-
grapholide and evaluated their anti-HBV activity. They
reported that andrographolide and some of its derivates not
only inhibit HBsAg and hepatitis B envelope antigen
(HBeAg) secretion but also exhibit anti-HBV effects by
inhibiting HBV DNA replication [55]. They also investi-
gated the relationship of the structure and anti-HBV
activity of andrographolide and its derivatives.
Hepatitis C virus
Hepatitis C virus (HCV) is a single-strand, positive-
sense RNA virus belonging to the family Flaviviridae,
genus Hepacivirus. HCV mostly infects hepatocytes, and
recently,HCVwasalsofoundtoinfectperipheral
mononuclear lymphocytes, especially B cells expressing
CD81 molecules [56]. HCV infection of the liver causes
chronic hepatitis, liver cirrhosis, and hepatocellular car-
cinoma and extrahepatic infection results in B-cell non-
Hodgkin lymphoma. HCV is about 55-65 nm in diameter
and contains a genome of approximately 9.6 kb. The
HCV genome encodes 10 viral proteins. The viral
structural proteins include the capsid and envelope gly-
coproteins E1 and E2. In the polyprotein precursor, the
NS protein p7 separates the structural proteins from the
other NS proteins and has viroporin activity. Other NS
proteins include NS2, NS3, NS4A, NS4B, NS5A and
NS5B, which are involved in viral replication and
polyprotein processing.
Host-pathogen interactions provide the stimulation to
the host immune system that is required for virus clearance.
HCV infection can activate the production of IFNs, which
restrict virus propagation. However, HCV has developed
strategies to counter host antiviral immune responses. In
order to inhibit IFN production, HCV NS4B suppresses
stimulator of IFN gene [57]. Immune cells such as CTLs
can also restrict virus multiplication inside the host.
Although CTLs can limit HCV replication, these cells are
also responsible for liver damage, leading to chronic HCV
infection [58]. Therefore, antiviral drugs with bivalent
action are required that can limit virus replication and can
also stimulate a host antiviral immune response.
Many anti-HCV drugs have been designed and tested for
their viral polymerase, NS3/4A protease and cyclophilin
inhibition activities [59]. The ability of HCV to develop
resistance very rapidly has led to a further rising demand
for new anti-HCV drugs. Lee et al. combined andro-
grapholide with IFN-a, telaprevir (HCV NS3/4A protease
inhibitor), and PSI-7977 (an inhibitor targeting HCV NS5B
polymerase) in an attempt to develop an effective antiviral
drug [60]. They reported significant synergistic effects of
andrographolide with these drugs. Andrographolide
increased haeme oxygenase-1 (HO-1) and as a result, liver
biliverdin increased, which suppressed HCV replication by
enhancing the IFN response and inhibited NS3/4A protease
activity. Andrographolide also activated p38 MAPK
phosphorylation, which led to the activation of nuclear
factor erythroid 2-related factor 2 (Nrf2)- mediated HO-1
expression, which was also linked to anti-HCV activity.
Chandramohan et al. also predicted andrographolide to be a
potent inhibitor of wild-type HCV NS3/4A protease and its
drug-resistant mutants R155K and D168A through
molecular docking studies [61]. Molecular docking simu-
lations also showed andrographolide to have good target-
protein binding ability and to maintain strong bonds,
causing little disturbance of the protein backbone structure.
The multiple modes of action of andrographolide in
restraining HCV activity shows that this compound is a
promising candidate for advanced research.
Herpes simplex virus 1 (HSV-1)
Herpes simplex virus 1 belongs to the family Herpesviri-
dae, genus Simplexvirus. It is an enveloped, double-stran-
ded DNA virus with a genome size of 152 kb and a
diameter of approximately 200 nm. HSV has four distinct
structural layers, which include an outermost envelope, a
matrix or tegument, an inner capsid of icosahedral sym-
metry, and the DNA core. HSV-1 DNA consists of two
unequal regions, i.e., a long (L) segment and a short
(S) segment and encodes over 80 proteins. The HSV-1
genes are divided into immediate early genes, early genes,
S. Gupta et al.
123
Author's personal copy
and late genes based on their order of transcription and
translation. HSV-1 infects skin and mucosal epithelial cells
and undergoes a lytic cycle, whereas in neuronal cells, it
becomes latent. HSV-1 infection leads to blister formation
on skin and mucosal membranes of the mouth, lips, geni-
tals and oesophagus. In the ocular region, HSV-1 infection
leads to conjunctivitis, keratitis, iridocyclitis, and acute
retinal necrosis [62].
The host defence against HSV infection includes both
innate and adaptive immune response. However, HSV-in-
fection inhibits phenotypic and functional maturation of
DCs subsequently resulting in reduced function of HSV
specific CD8
?
T cells [63]. The United States has licensed
drugs for the treatment of HSV infection, including acy-
clovir (ACV) for neonatal HSV disease, herpes simplex
encephalitis, mucocutaneous and viscerally disseminated
herpes infection. However, resistance to ACV can develop
due to mutations in the viral thymidine kinase. Another
FDA-approved drug for the treatment for acute herpes
zoster is famciclovir. However, similar to ACV, resistance
to famciclovir arises due to mutations in the viral thymi-
dine kinase gene [64]. To deal with the evolution of drug-
resistant forms, more antiviral drugs are required.
Andrographolide and other derivatives from A. panicu-
lata, such as neoandrographolide and 14-deoxy-11,12-
didehydroandrographolide (14-DDA), have been shown to
reduce the number of plaques formed by HSV-1 in Vero
cells [65]. Seubsasana et al. also showed that andro-
grapholide and 14-deoxyandrographolide (DAD) isolated
from A. paniculata and 3, 19-isopropylideneandro-
grapholide (IPAD), a semi-synthetic compound of andro-
grapholide inhibited HSV entry less than 50% [66].
However, post-infection administration of IPAD resulted in
100% inhibition of HSV infection, and this drug exhibited
anti-replication activity and reduced the expression of gp C
and gp D at all intervals of treatment. This study also
showed that IPAD did not have an inhibitory effect on the
immediate early step of viral replication, since inhibition
started at 4 h postinfection.
Aromdee et al. modified three free hydroxyls at C-3,
C-14 and C-19 of andrographolide, 14-DDA, DAD and
eight semisynthetic analogues and explored their anti-HSV
activity [67]. Their results confirmed that these three
hydroxyl moieties play an important role in the anti-HSV-1
activity of andrographolide. They also found that 14-acetyl
analogues block viral entry, whereas IPAD exerts post-
infection anti-HSV-1 activity. Priengprom et al. reported
the synergistic effects of the andrographolide analogue
IPAD with ACV against infection with wild-type HSV
(HSV-1 strain KOS and HSV-2 clinical isolate) and an
HSV-1 drug-resistant strain (HSV-1DR). They reported
that a non-cytotoxic concentration of IPAD (20.5 lM)
completely inhibited the cytopathic effect (CPE) caused by
wild-type HSV and HSV-1DR. A combination of IPAD
and ACV synergistically inhibited CPE, viral DNA repli-
cation, and protein synthesis in cells infected with wild-
type HSV and HSV-1DR [68].
Epstein-Barr virus (EBV)
Epstein-Barr virus belongs to the family Herpesviridae
and genus Lymphocryptovirus. EBV is a 120- to 150-nm
linear double-stranded DNA virus that produces virions
with icosahedral symmetry. The EBV NC is about
100-200 nm in diameter and contains a genome of
172 kb. EBV infects B cells and epithelial cells of
salivary glands, and under some circumstances it can
also infect T cells, NK cells and smooth muscle cells.
Transmission of virus takes place through blood, saliva
and genital secretions. It is a major cause of ‘‘kissing
disease’’, or mononucleosis, as the virus is mostly
transmitted through the saliva of an infected person.
EBV can be transmitted within epithelial cells through
contact by the formation of cell-in-cell structures
[69,70]. In epithelial cells, the virus undergoes repli-
cation and finally completes the lytic cycle, resulting in
transmission of virus to B cells.
EBV infection causes fatigue, rash, sore throat, swollen
glands, weakness, and other symptoms. Along with acute
infectious mononucleosis, EBV also causes nasopharyn-
geal carcinoma, Burkitt’s lymphoma, Hodgkin’s lym-
phoma, gastric carcinoma, multiple sclerosis, and
lymphomatoid granulomatosis. EBV not only evades
immune attack by infecting immune cells but has also
evolved other strategies to deal with it. EBV latent mem-
brane proteins are involved in activation and proliferation
of infected B cells. These proteins also reduce the activity
of CD8
?
T cells against EBV-infected cells [71]. Fur-
thermore, EBV inhibits the differentiation of DCs derived
from cord blood monocytes and induces apoptosis in a
caspase-dependent manner [72].
EBV expresses two transcription factors, Rta and Zta, in
the immediate early stage of the lytic cycle, which activate
early and late gene transcription and are required for
completion of the lytic cycle. To inhibit EBV propagation,
it is necessary to inhibit the expression of these two pro-
teins. Andrographolide has been tested against EBV in a
Burkitt’s lymphoma cell line using chemical stimulators of
the lytic cycle. Lin et al. tested both A. paniculata (25 lg
of ethanolic extract per ml) and andrographolide (5 lg/ml),
and both of them were found to inhibit EBV lytic proteins,
i.e., Rta, Zta and EA-D. Further studies revealed that the
lack of expression of these lytic proteins was due to inhi-
bition of transcription of two immediate-early genes:
BRLF1 (which codes for Rta) and BZLF1(which codes for
Zta) [73].
Andrographolide as an antiviral agent
123
Author's personal copy
Human papillomavirus (HPV)
Human papillomavirus is a small non-enveloped DNA
virus with a diameter of about 55 nm. HPV belongs to the
family Papillomaviridae and genus Alphapapillomavirus.
The HPV capsid is icosahedral in symmetry, and contains a
double-stranded circular DNA genome of about 8 kb. The
HPV genome consists of three regions, namely, the early
region, encoding NS genes involved in virus replication
and inhibition of tumor suppressor proteins, the late region,
encoding structural genes, and the regulatory region, con-
taining the origin of DNA replication and elements regu-
lating DNA replication. HPV is transmitted through
vaginal, anal and oral sex and enters cells via clathrin-
mediated endocytosis. HPV infects basal epithelial cells
through wounds and abrasions and causes genital warts and
cancer in the cervical, vulvar, vaginal, penile, anal, and
oropharyngeal regions.
HPV in order to escape from immune attack, affects the
differentiation of immune cells, leading to immune toler-
ance. The modifications induced by HPV include tumor-
associated macrophage differentiation, a compromised
cellular immune response, Th1-Th2 cell imbalance, T
reg
infiltration, and downregulation activation and maturation
of DCs [74]. However, vaccines based on delivery of the
L1 gene of HPV (AcHERVHPV) have been screened in
cell lines and mouse models and found to elicit a strong
cellular and humoral immune response [75]. Further
compounds suppressing the viral genes and revitalizing the
tumor suppressor proteins can provide the promising
antiviral effects against HPV.
Andrographolide has been tested for anti-HPV activity.
Ekalasananan et al. examined the effects of andro-
grapholide and its derivatives IPAD and 14-DDA on
HPV16 pseudovirus (HPV16PsVs), HPV E6 oncogene
expression, and cervical cancer cell apoptosis [76]. They
reported that the inhibitory effects of andrographolide and
its derivatives on HPV16 infection include inhibition of the
E6 oncogene, restoration of p53 tumor suppressor protein,
and induction of cervical cell apoptosis. They also reported
that andrographolide and its derivatives prevented the
binding of HPV16PsVs to host-cell receptors, and 14-DDA
showed the highest potency of post-attachment inhibition.
Human immunodeficiency virus (HIV)
Human immunodeficiency virus belongs to the family
Retroviridae and genus Lentivirus. HIV is a positive-sense,
enveloped RNA virus containing two identical copies of a
single-stranded RNA genome, each of 9181 bp. HIV is a
spherical virus with a diameter of about 120 nm. In the
early stages, HIV infection is M- tropic, i.e., infecting
macrophages (including monocytes, DCs and microglial
cells) expressing the CD4 receptor and CCR5 coreceptor.
In the middle phase of infection, HIV is dual tropic, i.e.,
infecting macrophages and T cells expressing CD4, CCR5
and CXCR4. At the late phase of infection, HIV is T-tropic,
i.e., showing preference for T cells expressing the CD4 and
CXCR4 receptors. HIV is transmitted through unprotected
sex, blood transfusion, and infected needles. Mother-to-
child transfer of HIV can take place during pregnancy,
labour, delivery, and breast feeding. Infection of immune
cells with HIV leads to acquired immunodeficiency syn-
drome (AIDS). Along with pain, fever and other virus-
associated symptoms, HIV patients may develop oppor-
tunistic infections due to a weakened immune system [77].
Combinations of antiviral drugs are given to HIV
patients (anti-retroviral therapy), which reduce HIV-in-
duced morbidity and mortality. However, emergence of
viral resistance has shifted the focus towards developing
new drugs against HIV. Various studies have been carried
out to test the anti-HIV activity of andrographolide. Chang
et al. reported the anti-HIV activity of a succinyl derivative
of andrographolide, dehydroandrographolide succinic acid
monoester (DASM), in H9 cells and human PBMCs [78].
They found that DASM exhibits anti-HIV effects by
interfering with the binding of HIV virions to cells and by
obstructing a step in the viral replication cycle subsequent
to virus-cell binding. Calabrese et al. conducted a phase I
trial of andrographolide in HIV-infected patients and found
a significant increase in CD4
?
lymphocytes on treatment
with andrographolide. The higher dose of andrographolide
also reduced the HIV RNA copy number, but this decrease
was not significant [79]. This study showed that andro-
grapholide, rather than inhibiting the virus directly, inhibits
the virus-induced dysregulation of cell signaling pathways.
p24 antigen is a viral protein that makes the viral capsid
or core, and its expression is highest during the early phase
of infection p24 antigen. Reddy et al. reported that
andrographolide and other compounds isolated from A.
paniculata reduced the level of p24 antigen in MT2 cell
line [80].
Chikungunya virus (CHIKV)
Chikungunay virus belongs to the family Togaviridae,
genus Alphavirus. It is an enveloped single-stranded posi-
tive-sense RNA virus with a diameter of about 60-70 nm.
The RNA genome, which is about 11.805 kb long, is
capped at the 50end and has a 30polyA tail. The 49S
CHIKV genome is first translated to produce NS proteins,
which form the viral replicase and help in RNA genome
replication and formation of 26S subgenomic RNA for
structural protein translation [81].
Chikungunya virus is an arbovirus that is spread by
Aedes mosquitoes. When an infected mosquito bites its
S. Gupta et al.
123
Author's personal copy
primate host, CHIKV enters the host through the mosquito
saliva and starts its replication in epithelial, endothelial,
fibroblast, monocyte and macrophage cells [82]. CHIKV
targets the joints, muscle, and skin, and rarely, the liver,
kidneys, eyes and central nervous system (CNS). A blood
meal from the infected host allows further transmission of
the virus to an uninfected mosquito, which can later
transmit CHIKV to a new host. CHIKV infection leads to
the fever, headache, rashes, myalgia, and polyarthralgia,
and the symptoms of myalgia and arthralgia can last for
years.
Due to the lack of effective anti-chikungunya drugs, only
the symptoms of disease can be treated. Wintachai et al.
reported the anti-CHIKV activity of andrographolide in
HepG2 and BHK-21 cells and found a decrease in the
CHIKV RNA copy number and CHIKV protein expression
[83]. They showed that andrographolide exerts an anti-
CHIKV effects at a post-entry step and effectively inhibits
viral genome replication. Our unpublished data also supports
the in vitro and in vivo anti-CHIKV activity of andro-
grapholide. We conducted our study on human monocytic
cells and in mouse neonates, and both experimental models
confirmed the potency of andrographolide as anti-CHIKV
agent. Moreover, we also observed immunomodulatory
activity of andrographolide in CHIKV-infected human
PBMCs and the results showed a strengthening effect of
andrographolide on host innate immune cells. Andro-
grapholide induced RIG-1 and PKR expression in CHIKV-
infected cells, highlighting its anti-CHIKV effects and
antiviral mechanism of action against CHIKV infection.
Future perspectives and conclusion
Global warming, climate change, drought, flood, host
migration, and vector distribution provide pressure for the
emergence of new viruses. Emerging and re-emerging viral
diseases have become a global threat. Therefore, there is an
urgent need to control viral infections, making it necessary
to understand the mechanisms that viruses use to evade the
host immune system and the manner in which they over-
take and utilize the host machinery to replicate and persist.
Antiviral vaccines stimulate immunity against viruses
by the administration of live attenuated virus or viral
subunits or peptides. However, these vaccines lose their
efficacy if the antigenicity of the virus changes. Moreover,
vaccines have limited therapeutic effects. Plant-based
Fig. 3 Inhibitory effects of andrographolide on the viral life cycle
Andrographolide as an antiviral agent
123
Author's personal copy
antiviral drugs have provided great hope for combating the
viral infection (Fig. 3). They target viral receptor and co-
receptor binding [8487], fusion and adsorption to the cell
[8893], virus replication [94,95], reverse transcription
and integration [9698], viral protein translation [99] and
post-translational modifications [100,101]. The prevalence
of infectious diseases in developing countries requires cost-
effective antiviral drugs with high efficacy. Some plant-
derived antiviral drugs fulfill this challenge by being cost-
effective, easily available, low in cytotoxicity, and thera-
peutically effective against viral infections. Andro-
grapholide, a plant-derived compound is widely
distributed, is cost-effective, has low cytotoxicity and has
been shown to have antiviral activity against a number of
viral infections. However, much research is needed to
identify its target molecules in the viral life cycle.
Recently, a whole extract of A. paniculata was tested
against dengue virus and simian retrovirus infections
[102,103]. Moreover, Edwin et al. also suggested a role for
andrographolide in the management of the dengue virus
and chikungunya virus vector Aedes aegypti.[104].
Andrographolide assists in vector management by reducing
oviposition, causing CPE in the midgut epithelium, and
increasing larvicidal activity. However, additional research
is required to establish the role of this bioactive compound
in other viral infections. Plants are a good source of
bioactive compounds for antiviral drug development
[105,106], and recent studies on the unfolded protein
response pathway suggest that it could be an important
target of various plant-derived drugs [107111]. Andro-
grapholide, being a strong immunomodulator, can also be
tested in combination therapies to treat infectious diseases.
Andrographolide appears to be effective against a variety
of viral infections, and in the future, it can be used in drug
development, either alone or in combination, for the inhi-
bition of virus infection and treatment of infectious
diseases.
Acknowledgements This work was supported by the Council of
Scientific and Industrial Research (CSIR) in the form of a research
fellowship granted to SG and the Defence Research and Development
Organisation (DRDO) in the form of a project grant.
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.
References
1. Liu R, Jacob JR, Tennant B (2003) United States patent,
Andrographolide derivatives to treat viral infections, vol 1(12)
2. Shao Z-J, Zheng X-W, Feng T, Huang J, Chen J, Wu Y-Y et al
(2012) Andrographolide exerted its antimicrobial effects by
upregulation of human b-defensin-2 induced through p38
MAPK and NF-jB pathway in human lung epithelial cells. Can
J Physiol Pharmacol 90(5):647–653
3. Arifullah M, Namsa ND, Mandal M, Chiruvella KK, Vikrama P,
Gopal GR (2013) Evaluation of anti-bacterial and anti-oxidant
potential of andrographolide and echiodinin isolated from callus
culture of Andrographis paniculata Nees. Asian Pac J Trop
Biomed 3(8):604–610
4. Hua Z, Frohlich KM, Zhang Y, Feng X, Zhang J, Shen L (2015)
Andrographolide inhibits intracellular Chlamydia trachomatis
multiplication and reduces secretion of proinflammatory medi-
ators produced by human epithelial cells. Pathog Dis 73(1):1–11
5. Roy P, Das S, Bera T, Mondol S, Mukherjee A (2010) Andro-
grapholide nanoparticles in leishmaniasis: characterization and
in vitro evaluations. Int J Nanomed 5(1):1113–1121
6. Mishra K, Dash AP, Dey N (2011) Andrographolide: a novel
antimalarial diterpene lactone compound from Andrographis
paniculata and its interaction with curcumin and artesunate.
J Trop Med 2011:579518
7. Zaid OI, Abd Majid R, Sabariah MN, Hasidah MS, Al-Zihiry K,
Yam MF et al (2015) Andrographolide effect on both Plas-
modium falciparum infected and non infected RBCs membranes.
Asian Pac J Trop Med 8(7):507–512
8. Jayakumar T, Hsieh CY, Lee JJ, Sheu JR (2013) Experimental
and clinical pharmacology of Andrographis paniculata and its
major bioactive phytoconstituent andrographolide. Evid based
ComplemAltern Med 2013
9. Alagesaboopathi C (2000) Andrographis spp: a source of bitter
compounds for medicinal use. Anc Sci Life 19(3 & 4):164–168
10. Bao Z, Guan S, Cheng C, Wu S, Wong SH, Michael Kemeny D
et al (2009) A novel antiinflammatory role for andrographolide
in asthma via inhibition of the nuclear factor-jb pathway. Am J
Respir Crit Care Med 179(8):657–665
11. Chen Y-YY, Hsu M-JJ, Hsieh C-YY, Lee L-WW, Chen Z-CC,
Sheu J-RR (2013) Andrographolide inhibits nuclear factor-jB
activation through JNK-Akt-p65 signaling cascade in tumor
necrosis factor-a-stimulated vascular smooth muscle cells. Sci
World J 2014:130381
12. Chao CY, Lii CK, Tsai IT, Li CC, Liu KL, Tsai CW et al (2011)
Andrographolide inhibits ICAM-1 expression and NF-jB acti-
vation in TNF-a-treated EA.hy926 cells. J Agric Food Chem
59(10):5263–5271
13. Xia Y-F, Ye B-Q, Li Y-D, Wang J-G, He X-J, Lin X et al (2004)
Andrographolide attenuates inflammation by inhibition of NF-
kappa B activation through covalent modification of reduced
cysteine 62 of p50. J Immunol (Baltimore, Md: 1950)
173(6):4207–4217
14. Shanmugam M, Singh AK, Nagarethinam B, Sekar K (2012)
Pro-apoptotic and anti-inflammatory potential of andro-
grapholide during 7, 12-dimethylbenz [a] anthracene induced
hamster buccal pouch carcinogenesis. Integr Med 2(4):313–319
15. Lin HH, Der Shi M, Tseng HC, Chen JH (2014) Andro-
grapholide sensitizes the cytotoxicity of human colorectal car-
cinoma cells toward cisplatin via enhancing apoptosis pathways
in vitro and in vivo. Toxicol Sci 139(1):108–120
16. Yunos NM, Mutalip SSM, Jauri MH, Yu JQ, Huq F (2013) Anti-
proliferative and pro-apoptotic effects from sequenced combi-
nations of andrographolide and cisplatin on ovarian cancer cell
lines. Anticancer Res 33(10):4365–4372
17. Zhou J, Zhang S, Ong C-N, Shen H-M (2006) Critical role of
pro-apoptotic Bcl-2 family members in andrographolide-in-
duced apoptosis in human cancer cells. Biochem Pharmacol
72(2):132–144
18. Yang S, Evens AM, Prachand S, Singh ATK, Bhalla S, David K
et al (2010) Mitochondrial-mediated apoptosis in lymphoma
cells by the diterpenoid lactone andrographolide, the active
S. Gupta et al.
123
Author's personal copy
component of Andrographis paniculata. Clin Cancer Res
16(19):4755–4768
19. Li G-F, Qin Y-H, Du P-Q (2015) Andrographolide inhibits the
migration, invasion and matrix metalloproteinase expression of
rheumatoid arthritis fibroblast-like synoviocytes via inhibition of
HIF-1asignaling. Life Sci 136:67–72
20. Pratheeshkumar P, Kuttan G (2011) Andrographolide inhibits
human umbilical vein endothelial cell invasion and migration by
regulating MMP-2 and MMP-9 during angiogenesis. J Environ
Pathol Toxicol Oncol 30(1):33–41
21. Zhai Z, Qu X, Li H, Ouyang Z, Yan W, Liu G et al (2015)
Inhibition of MDA-MB-231 breast cancer cell migration and
invasion activity by andrographolide via suppression of nuclear
factor-jB-dependent matrix metalloproteinase-9 expression.
Mol Med Rep 11(2):1139–1145
22. Shi MD, Lin HH, Chiang TA, Tsai LY, Tsai SM, Lee YC et al
(2009) Andrographolide could inhibit human colorectal carci-
noma Lovo cells migration and invasion via down-regulation of
MMP-7 expression. Chem Biol Interact 180(3):344–352
23. Lee Y-C, Lin H-H, Hsu C-H, Wang C-J, Chiang T-A, Chen J-H
(2010) Inhibitory effects of andrographolide on migration and
invasion in human non-small cell lung cancer A549 cells via
down-regulation of PI3K/Akt signaling pathway. Eur J Phar-
macol 632(1–3):23–32
24. Sheeja K, Kuttan G (2007) Activation of cytotoxic T lympho-
cyte responses and attenuation of tumor growth in vivo by An-
drographis paniculata extract and andrographolide.
Immunopharmacol Immunotoxicol 29(1):81–93
25. Iruretagoyena MI, Tobar JA, Gonza
´lez PA, Sepu
´lveda SE,
Figueroa CA, Burgos RA et al (2005) Andrographolide inter-
feres with T cell activation and reduces experimental autoim-
mune encephalomyelitis in the mouse. J Pharmacol Exp Therap
312(1):366–372
26. Chan SJ, Wong WSF, Wong PTH, Bian JS (2010) Neuropro-
tective effects of andrographolide in a rat model of permanent
cerebral ischaemia. Br J Pharmacol 161(3):668–679
27. Das S, Gautam N, Dey SK, Maiti T, Roy S (2009) Oxidative
stress in the brain of nicotine-induced toxicity: protective role of
Andrographis paniculata Nees and vitamin E. Appl Physiol Nutr
Metab (Physiol Appl Nutr Metab) 34(2):124–135
28. Chen H-W, Huang C-S, Li C-C, Lin A-H, Huang Y-J, Wang T-S
et al (2014) Bioavailability of andrographolide and protection
against carbon tetrachloride-induced oxidative damage in rats.
Toxicol Appl Pharmacol 280(1):1–9
29. Singha PK, Roy S, Dey S (2007) Protective activity of andro-
grapholide and arabinogalactan proteins from Andrographis
paniculata Nees against ethanol-induced toxicity in mice.
J Ethnopharmacol 111(1):13–21
30. Zhang Z, Shi G, Zhang Z, Zhang R, Zhang X, Lu Y et al (2012)
Protective effect of andrographolide against concanavalin
A-induced liver injury. Naunyn-Schmiedeberg’s Arch Pharma-
col 385(1):69–79
31. Roy P, Das S, Auddy RG, Mukherjee A (2014) Engineered
andrographolide nanosystems for smart recovery in hepatotoxic
conditions. Int J Nanomed 9:4723–4735
32. Xu Y, Chen A, Fry S, Barrow RA, Marshall RL, Mukkur TKS
(2007) Modulation of immune response in mice immunised with
an inactivated Salmonella vaccine and gavaged with Andro-
graphis paniculata extract or andrographolide. Int
Immunopharmacol 7(4):515–523
33. Naik SR, Hule A (2009) Evaluation of immunomodulatory
activity of an extract of andrographolides from Andographis
paniculata. Planta Med 75(8):785–791
34. Carretta MD, Alarco
´n P, Jara E, Solis L, Hancke JL, Concha II
et al (2009) Andrographolide reduces IL-2 production in T-cells
by interfering with NFAT and MAPK activation. Eur J Phar-
macol 602(2–3):413–421
35. Sheeja K, Kuttan G (2007) Modulation of natural killer cell
activity, antibody-dependent cellular cytotoxicity, and antibody-
dependent complement-mediated cytotoxicity by andro-
grapholide in normal and Ehrlich ascites carcinoma-bearing
mice. Integr Cancer Ther 6(1):66–73
36. Peng G, Zhou F, Ding R, Li H, Yao K (2002) Modulation of
lianbizi injection (andrographolide) on some immune functions.
Zhongguo zhongyao zazhi (China J Chin Mater Med)
27(2):147–150
37. Lindsley WG, Noti JD, Blachere FM, Thewlis RE, Martin SB,
Othumpangat S et al (2015) Viable influenza a virus in airborne
particles from human coughs. J Occup Environ Hyg
12(2):107–113
38. Goto H, Muramoto Y, Noda T, Kawaoka Y (2013) The genome
packaging signal of the influenza A virus genome comprises a
genome incorporation signal and a genome bundling signal.
J Virol 87(21):11316–11322
39. Nicholson K, Robert G, Webster AJH (eds) (2013) Textbook of
influenza. Blackwell Science, New York
40. Ruangrung K, Suptawiwat O, Maneechotesuwan K et al (2016)
Neuraminidase activity and resistance of 2009 pandemic H1N1
influenza virus to antiviral activity in bronchoalveolar fluid.
J Virol 90(9):4637–4646. doi:10.1128/JVI.00013-16
41. Chen J-X, Xue H-J, Ye W-C, Fang B-H, Liu Y-H, Yuan S-H
et al (2009) Activity of andrographolide and its derivatives
against influenza virus in vivo and in vitro. Biol Pharmaceut
Bull 32(August):1385–1391
42. Raja K, Prabahar A, Selvakumar S, Raja TK (2014) In silico
analysis to compare the effectiveness of assorted drugs pre-
scribed for swine flu in diverse medicine systems. Indian J
Pharmaceut Sci 76(1):10–18
43. La
¨ssig C, Hopfner KP (2016) RIG-I-like receptors: one STrEP
forward. Trends Microbiol 24(7):517–519. doi:10.1016/j.tim.
2016.05.001 (Epub 2016 May 25)
44. Yu B, Dai C, Jiang Z, Li E, Chen C, Wu X et al (2014)
Andrographolide as an anti-H1N1 drug and the mechanism
related to retinoic acid-inducible gene-I-like receptors signaling
pathway. Chin J Integr Med 20(7):540–545
45. Yuan L, Zhang C, Sun H, Liu Q, Huang J, Sheng L et al (2016)
The semi-synthesis of novel andrographolide analogues and
anti-influenza virus activity evaluation of their derivatives.
Bioorgan Med Chem Lett 26(3):769–773
46. Ca
´ceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK
(1999) Use of visual analogue scale measurements (VAS) to
asses the effectiveness of standardized Andrographis paniculata
extract SHA-10 in reducing the symptoms of common cold. A
randomized double blind-placebo study. Phytomedicine
6(4):217–223
47. Hong M, Sandalova E, Low D et al (2015) Trained immunity in
newborn infants of HBV-infected mothers. Nat Commun
25(6):6588. doi:10.1038/ncomms7588
48. Gitlin N (1997) Hepatitis B: diagnosis, prevention, and treat-
ment. Clin Chem 43(8 Pt 2):1500–1506
49. Sa-Nguanmoo P, Rianthavorn P, Amornsawadwattana S,
Poovorawan Y (2009) Hepatitis B virus infection in non-human
primates. Acta Virol 53(2):73–82
50. Stoop JN, van der Molen RG, Baan C et al (2005) Regulatory T
cells contribute to the impaired immune response in patients
with chronic hepatitis B virus infection. Hepatology
41:771–778. doi:10.1002/hep.20649
51. Busca A, Kumar A (2014) Innate immune responses in hepatitis
B virus (HBV) infection. Virol J 11(1):22
Andrographolide as an antiviral agent
123
Author's personal copy
52. Chen Y, Zhu J (2013) Anti-HBV effect of individual traditional
Chinese herbal medicine in vitro and in vivo: an analytic review.
J Viral Hepat 2013:445–452
53. Huang Q, Zhang S, Huang R, Wei L, Chen Y, Lv S et al (2013)
Isolation and identification of an anti-hepatitis B virus com-
pound from Hydrocotyle sibthorpioides Lam. J Ethnopharmacol
150(2):568–575
54. Kim KH, Kim ND, Seong BL (2010) Discovery and develop-
ment of anti-HBV agents and their resistance. Molecules
15(9):5878–5908
55. Chen H, Ma Y-B, Huang X-Y, Geng C-A, Zhao Y, Wang L-J
et al (2014) Synthesis, structure–activity relationships and bio-
logical evaluation of dehydroandrographolide and andro-
grapholide derivatives as novel anti-hepatitis B virus agents.
Bioorgan Med Chem Lett 24(10):2353–2359
56. Ito M, Kusunoki H, Mizuochi T (2011) Peripheral B cells as
reservoirs for persistent HCV infection 2:1–3
57. Yi G, Wen Y, Shu C et al (2015) Hepatitis C virus NS4B can
suppress STING accumulation to evade innate immune
responses. J Virol 90(1):254–265. doi:10.1128/JVI.01720-15
58. Freeman AJ, Marinos G, Ffrench RA, Lloyd AR (2001)
Immunopathogenesis of hepatitis C virus infection. Immunol
Cell Biol 79(6):515–536
59. Yu Y, Jing JF, Tong XK, He PL, Li YC, Hu YH et al (2014)
Discovering novel anti-HCV compounds with inhibitory activ-
ities toward HCV NS3/4A protease. Acta Pharmacol Sin
35(8):1074–1081
60. Lee JC, Tseng CK, Young KC, Sun HY, Wang SW, Chen WC
et al (2014) Andrographolide exerts anti-hepatitis C virus
activity by up-regulating haeme oxygenase-1 via the p38
MAPK/Nrf2 pathway in human hepatoma cells. Br J Pharmacol
171(1):237–252
61. Chandramohan V, Kaphle A, Chekuri M, Gangarudraiah S,
Bychapur Siddaiah G (2015) Evaluating andrographolide as a
potent inhibitor of NS3-4A protease and its drug-resistant
mutants using in silico approaches. Adv Virol 2015
62. Farooq AV, Valyi-Nagy T, Shukla D (2010) Mediators and
mechanisms of herpes simplex virus entry into ocular cells. Curr
Eye Res 35(6):445–450
63. Chentoufi AA, Dervillez X, Dasgupta G et al (2012) The herpes
simplex virus type 1 latency-associated transcript inhibits phe-
notypic and functional maturation of dendritic cells. Viral
Immunol 25(3):204–215. doi:10.1089/vim.2011.0091
64. Kimberlin DW, Whitley RJ (2007) Antiviral therapy of HSV-1
and HSV-2. In: Arvin A, Campadelli-Fiume G, Mocarski E et al
(eds) Human herpesviruses: biology, therapy, and immunopro-
phylaxis, chap 64. Cambridge University Press, Cambridge
65. Wiart C, Kumar K, Yusof MY, Hamimah H, Fauzi ZM, Sulai-
man M (2005) Antiviral properties of ent-labdene diterpenes of
Andrographis paniculata Nees, inhibitors of herpes simplex
virus type 1. Phytother Res 19(August):1069–1070
66. Seubsasana S, Pientong C, Ekalaksananan T, Thongchai S,
Aromdee C (2011) A potential andrographolide analogue
against the replication of herpes simplex virus type 1 in vero
cells. Med Chem 7(3):237–244
67. Aromdee C, Suebsasana S, Ekalaksananan T, Pientong C,
Thongchai S (2011) Stage of action of naturally occurring
andrographolides and their semisynthetic analogues against
herpes simplex virus type 1 in vitro. Planta Med
77(9):915–921
68. Priengprom T, Ekalaksananan T, Kongyingyoes B, Suebsasana
S, Aromdee C, Pientong C (2015) Synergistic effects of acy-
clovir and 3, 19-isopropylideneandrographolide on herpes sim-
plex virus wild types and drug-resistant strains. BMC
Complement Altern Med 15(1):56
69. Tugizov SM, Berline JW, Palefsky JM (2003) Epstein–Barr
virus infection of polarized tongue and nasopharyngeal epithe-
lial cells. Nat Med 9(3):307–314
70. Ni C, Chen Y, Zeng M, Pei R, Du Y, Tang L et al (2015) In-cell
infection: a novel pathway for Epstein–Barr virus infection
mediated by cell-in-cell structures. Cell Res 25(7):785–800
71. Rancan C, Schirrmann L, Hu
¨ls C, Zeidler R, Moosmann A
(2015) Latent membrane protein LMP2A impairs recognition of
EBV-infected cells by CD8?T cells. PLoS Pathog
11(6):e1004906. doi:10.1371/journal.ppat.1004906
72. Wang JJ, Li YF, Jin YY, Wang X, Chen TX (2012) Effects of
Epstein–Barr virus on the development of dendritic cells derived
from cord blood monocytes: an essential role for apoptosis. Braz
J Infect Dis 16(1):19–26
73. Lin T-P, Chen S-Y, Duh P-D, Chang L-K, Liu Y-N (2008)
Inhibition of the Epstein–Barr virus lytic cycle by andro-
grapholide. Biol Pharmaceut Bull 31(11):2018–2023
74. Song D, Li H, Li H, Dai J (2015) Effect of human papillo-
mavirus infection on the immune system and its role in the
course of cervical cancer. Oncol Lett 10(2):600–606 (Epub
2015 May 29)
75. Lee HJ, Yoon JK, Heo Y, Cho H, Cho Y, Gwon Y, Kim KC,
Choi J, Lee JS, Oh YK, Kim YB (2015) Therapeutic potential of
an AcHERV-HPV L1 DNA vaccine. J Microbiol
53(6):415–420. doi:10.1007/s12275-015-5150-0
76. Ekalaksananan T, Sookmai W, Fangkham S, Pientong C,
Aromdee C, Seubsasana S et al (2015) Activity of andro-
grapholide and its derivatives on HPV16 pseudovirus infection
and viral oncogene expression in cervical carcinoma cells. Nutr
Cancer 67(4):687–696
77. Masur H (2015) HIV-related opportunistic infections are still
relevant in 2015. Top Antivir Med 23(3):116–119
78. Chang RS, Ding L, Chen GQ, Pan QC, Zhao ZL, Smith KM
(1991) Dehydroandrographolide succinic acid monoester as an
inhibitor against the human immunodeficiency virus. Proc Soc
Exp Biol Med 197(1):59–66
79. Calabrese C, Berman SH, Babish JG, Ma X, Shinto L, Dorr M
et al (2000) A phase I trial of andrographolide in HIV positive
patients and normal volunteers. Phytother Res PTR
14(5):333–338
80. Reddy VLN, Reddy SM, Ravikanth V (2014) Natural product
research : formerly natural product letters a new BIS-andro-
grapholide ether from Andrographis paniculata Nees and eval-
uation of anti-HIV activity. J Asian Nat Prod Res 2006:37–41
81. van Duijl-Richter M, Hoornweg T, Rodenhuis-Zybert I, Smit J
(2015) Early events in chikungunya virus infection—from virus
cell binding to membrane fusion. Viruses 7(7):3647–3674
82. Thon-Hon VG, Denizot M, Li-Pat-Yuen G, Giry C, Jaffar-
Bandjee M-C, Gasque P (2012) Deciphering the differential
response of two human fibroblast cell lines following chikun-
gunya virus infection. Virol J 9(1):213
83. Wintachai P, Kaur P, Lee RCH, Ramphan S, Kuadkitkan A,
Wikan N et al (2015) Activity of andrographolide against
chikungunya virus infection. Sci Rep Nat Publish Group
5:14179
84. Keyaerts E, Vijgen L, Pannecouque C, Van Damme E, Peumans
W, Egberink H et al (2007) Plant lectins are potent inhibitors of
coronaviruses by interfering with two targets in the viral repli-
cation cycle. Antiviral Res 75(3):179–187
85. Singh S, Shenoy S, Nehete PN, Yang P, Nehete B, Fontenot D
et al (2013) Nerium oleander derived cardiac glycoside olean-
drin is a novel inhibitor of HIV infectivity. Fitoterapia
84(1):32–39
86. Park IW, Han C, Song X, Green LA, Wang T, Liu Y et al (2009)
Inhibition of HIV-1 entry by extracts derived from traditional
S. Gupta et al.
123
Author's personal copy
Chinese medicinal herbal plants. BMC Complement Altern
Med. 9:29
87. Xue J, Gao Y, Hoorelbeke B, Kagiampakis I, Zhao B, Demeler
B et al (2012) The role of individual carbohydrate-binding sites
in the function of the potent anti-HIV lectin griffithsin. Mol
Pharmaceut 9(9):2613–2625
88. Chang Y-S, Woo E-R (2003) Korean medicinal plants inhibiting
to human immunodeficiency virus type 1 (HIV-1) fusion. Phy-
tother Res PTR 17(4):426–429
89. Talarico LB, Damonte EB (2007) Interference in dengue virus
adsorption and uncoating by carrageenans. Virology
363(2):473–485
90. Bankova V, Galabov AS, Antonova D, Vilhelmova N, Di Perri
B (2014) Chemical composition of Propolis Extract ACFÒand
activity against herpes simplex virus. Phytomedicine
21(11):1432–1438
91. Zandi K, Teoh B-T, Sam S-S, Wong P-F, Mustafa MR, Abu-
bakar S (2012) Novel antiviral activity of baicalein against
dengue virus. BMC Complement Altern Med 12(1):214
92. Haid S, Novodomsk A, Gentzsch J, Grethe C, Geuenich S,
Bankwitz D et al (2012) A plant-derived flavonoid inhibits entry
of All HCV genotypes into human hepatocytes. Gastroenterol-
ogy 143(1)
93. Blaising J, Lvy PL, Gondeau C, Phelip C, Varbanov M, Teissier
E et al (2013) Silibinin inhibits hepatitis C virus entry into
hepatocytes by hindering clathrin-dependent trafficking. Cell
Microbiol 15(11):1866–1882
94. Kim Y, Narayanan S, Chang KO (2010) Inhibition of influenza
virus replication by plant-derived isoquercetin. Antiviral Res
88(2):227–235
95. Wang YJ, Pan KL, Hsieh TC, Chang TY, Lin WH, Hsu JTA
(2011) Diosgenin, a plant-derived sapogenin, exhibits antiviral
activity in vitro against hepatitis C virus. J Nat Prod
74(4):580–584
96. Zhang X, Huang SZ, Gu WG, Yang LM, Chen H, Zheng CB
et al (2014) Wikstroelide M potently inhibits HIV replication by
targeting reverse transcriptase and integrase nuclear transloca-
tion. Chin J Nat Med 12(3):186–193
97. Rimando AM, Pezzuto JM, Farnsworth NR, Santisuk T, Reu-
trakul V, Kawanishi K (1994) New lignans from Anogeissus
acuminata with HIV-1 reverse transcriptase inhibitory activity.
J Nat Prod 57(7):896–904
98. Rowley DC, Hansen MST, Rhodes D, Sotriffer CA, Ni H,
McCammon JA et al (2002) Thalassiolins A–C: new marine-
derived inhibitors of HIV cDNA integrase. Bioorgan Med Chem
10(11):3619–3625
99. Mansouri S, Choudhary G, Sarzala PM, Ratner L, Hudak K
(2009) Suppression of human T-cell leukemia virus I gene
expression by pokeweed antiviral protein. J Biol Chem
284(45):31453–31462
100. Wan Z, Lu Y, Liao Q, Wu Y, Chen X (2012) Fangchinoline
inhibits human immunodeficiency virus type 1 replication by
interfering with gp160 proteolytic processing. PLoS One 7(6)
101. Narayan V, Ravindra KC, Chiaro C, Cary D, Aggarwal BB,
Henderson AJ et al (2011) Celastrol inhibits tat-mediated human
immunodeficiency virus (HIV) transcription and replication.
J Mol Biol 410(5):972–983
102. Nithya P, Jeyaram C, Sundaram KM, Chandrasekar A, Rama-
samy MS (2014) Anti-dengue viral compounds from Andro-
graphis paniculata by insilico approach indian system of
medicine / natural product. Laboratory 1(2):10–16
103. Pongtuluran OB, Rofaani E (2015) Antiviral and immunostim-
ulant activities of Andrographis paniculata. HAYATI J Biosci
22(2)
104. Edwin ES, Srinivasan V, Senthil-Nathan S, Thanigaivel PA,
Ponsankar A, Pradeepa V, Selin-Rani S, Kalaivani K, Hunter
WB, Abdel-Megeed A, Duraipandiyan V, Al-Dhabi NA (2016)
Anti-dengue efficacy of bioactive andrographolide from An-
drographis paniculata (Lamiales: Acanthaceae) against the
primary dengue vector Aedes aegypti (Diptera: Culicidae). Acta
Trop
105. Diwaker D, Mishra KP, Ganju L, Singh SB (2014) Rhodiola
inhibits dengue virus multiplication by inducing innate immune
response genes RIG-I, MDA5 and ISG in human monocytes.
Arch Virol 159(8):1975–1986
106. Mishra KP, Sharma N, Diwaker D, Ganju L, Singh SB (2016)
Plant derived antivirals: a potential source of drug development.
J Virol Antiviral Res 2(2)
107. Diwaker D, Mishra KP, Ganju L (2015) Effect of modulation of
unfolded protein response pathway on dengue virus infection.
Acta Biochim Biophys Sin (Shanghai) 47(12):960–968
108. Lazar C, Uta M, Branza-Nichita N (2014) Modulation of the
unfolded protein response by the human hepatitis B virus. Front
Microbiol 19(5):433
109. Kavaliauskis A, Arnemo M, Rishovd AL, Gjøen T (2016)
Activation of unfolded protein response pathway during infec-
tious salmon anemia virus (ISAV) infection in vitro an in vivo.
Dev Comp Immunol 54(1):46–54
110. Medigeshi GR, Lancaster AM, Hirsch AJ, Briese T, Lipkin WI,
Defilippis V, Fru
¨h K, Mason PW, Nikolich-Zugich J, Nelson JA
(2007) West Nile virus infection activates the unfolded protein
response, leading to CHOP induction and apoptosis. J Virol
81(20):10849–10860
111. Rathore AP, Ng ML, Vasudevan SG (2013) Differential unfol-
ded protein response during Chikungunya and Sindbis virus
infection: CHIKV nsP4 suppresses eIF2aphosphorylation. Virol
J 28(10):36
Andrographolide as an antiviral agent
123
Author's personal copy
... The most important bioactive compounds of A. paniculata are andrographolide (AG), 14-Deoxy-11,12-didehydroandrographolide (DDAG), and neoandrographolide (NAG) (Valdiani et al. 2017). The herb has shown important therapeutic properties, such as antiviral and anti-inflammatory (Gupta et al. 2017) as well as anticancer effects (Suriyo et al. 2021), mainly because of andrographolide. Different anticancer mechanisms of andrographolide, such as cell cycle arrest and apoptosis (Suriyo et al. 2014), NF-κβ inhibition (Mishra 2021), antiangiogenesis (Dai et al. 2017), cytochrome P400 and P450s regulation (Suriyo et al. 2021), and cytokine inhibition , have been compiled and reviewed, recently (Malik et al. 2021). ...
Article
In accordance with the importance of telomerase inhibition as a potential target in cancer therapy, and increasing reports on the association between short telomeres and severe COVID-19 symptoms as well as extensive application of Andrographis paniculata as a remedy for both cancer and SARS-CoV-2, the present study aimed at investigating the impact of the plant's extracts on telomerase activity (as an important enzyme regulating telomere length). Telomerase inhibition in MCF-7 cells treated with the Dichloromethane, ethanol, water, and methanol extracts of A. paniculata was assessed using Telomerase Repeated Amplification Protocol (TRAP). The above-mentioned extracts inhibited telomerase by 80.3 ± 1.4%, 78.5 ± 1.35%, 77.5 ± 1.81%, and 73.7 ± 1.81%, respectively. Furthermore, the flow cytometry analysis showed that the water and methanol extracts induced higher rates of total apoptosis by 32.8% and 25%, respectively, compared with dichloromethane (10.07%) and ethanol (10.7%) extracts. The inhibitory effect of A. paniculata on telomerase activity can be considered as a potential immunity modulator in cancer therapy; however, telomerase inhibition as a safe approach to SARS-CoV-2 is arguable. Two mechanisms can be considered accordingly; (a) reducing the existing population of short telomeres via telomerase inhibition in cancer cells (arresting proliferation and finally cell death) may decrease the susceptibility against SARS-CoV-2, especially in cancer patients or patients prone to cancer, and (b) increasing the population of short telomeres via telomerase inhibition in normal/somatic cells may increase the susceptibility against SARS-CoV-2. Therefore, the telomerase inhibition of A. paniculata as an immunity modulator in cancer and COVID-19 should be investigated, carefully.
... The andrographolide is a diterpene with known large anti-inflammatory activity and also has proved action against the viruses causing Influenza A, Hepatitis B, Hepatitis C, and Herpes Simplex. Among these substances, andrographolide is suggested to be a potential terpene for the treatment of SARS-CoV-2 due to its antiviral mechanism is the inhibition or reduction of binding protein's expression in these viruses [60]. More, artemisinin had promising results in docking analysis. ...
Article
Full-text available
Objective and design The current study aimed to summarize the evidence of compounds contained in plant species with the ability to block the angiotensin-converting enzyme 2 (ACE-II), through a scoping review. Methods PubMed and Scopus electronic databases were used for the systematic search and a manual search was performed Results Studies included were characterized as in silico. Among the 200 studies retrieved, 139 studies listed after the exclusion of duplicates and 74 were included for the full read. Among them, 32 studies were considered eligible for the qualitative synthesis. The most evaluated class of secondary metabolites was flavonoids with quercetin and curcumin as most actives substances and terpenes (isothymol, limonin, curcumenol, anabsinthin, and artemisinin). Other classes that were also evaluated were alkaloid, saponin, quinone, substances found in essential oils, and primary metabolites as the aminoacid l-tyrosine and the lipidic compound 2-monolinolenin. Conclusion This review suggests the most active substance from each class of metabolites, which presented the strongest affinity to the ACE-II receptor, what contributes as a basis for choosing compounds and directing the further experimental and clinical investigation on the applications these compounds in biotechnological and health processes as in COVID-19 pandemic.
... As the primary compound separated from aerial part of A. paniculata, andrographolide has been reported that it possesses a variety of pharmacological effects like antibacterial, anti-inflammatory, antiviral, antioxidation, anticancer and so on (Zhang et al. 2018;Mussard et al. 2019;Islam 2017;Gupta et al. 2017;Dai et al. 2019). Moreover, its cardiovascular protective effect and corresponding potential therapeutic action have drawn researchers wide attention (Maiti et al. 2006). ...
Preprint
Full-text available
Endothelial cell protein C (EPCR), one of the main members in the protein C (PC) pathway, plays an important role in the process of coagulation and inflammation. EPCR can shed from the cell membrane, which process is mediated by the tumor necrosis factor-α converting enzyme (TACE) and related to some diseases. Andrographolide is the major constituent of Andrographis paniculata, a kind of herbal medicine commonly used in clinical for its various pharmacological actions, especially anti-inflammation and anti-cancer. In this study, we investigated andrographolide protection for EPCR and its potential molecular mechanism. Phorbol-12-myristate-13-acetate (PMA)-stimulated human umbilical vein endothelial cells (HUVECs) were used to be the model of EPCR shedding and the andrographolide pretreatment was tested in this model. The results showed that andrographolide could reduce PMA-induced EPCR shedding and inhibit the TACE function. Additionally, we found andrographolide also suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38, but had no effect on extracellular regulated protein kinase (ERK) 1/2. Given these results, andrographolide can inhibit the shedding of EPCR by the suppression of TACE, which may take JNK and p38 as the molecular target. These findings indicated a substantial anti-EPCR shedding efficacy of andrographolide in vitro.
... It has been used extensively in China and Thailand for upper respiratory infections based on the results of clinical trials [112][113][114][115][116][117]. Andrographolide has the potential to be an effective anti-COVID-19 drug considering its antiviral, anti-inflammatory, and immunomodulatory [118,119] activities, as well as its safety profile [120,121]. Recent in vitro studies provided evidence to support the development of this drug for COVID-19 treatment [5,6]. ...
Article
Introduction The article aims to emphasize the necessity of proper research design, both scientifically and ethically, in order to provide good evidence for physicians to base their decisions on when prescribing drug treatment. Material and methods Research articles and guidelines related to therapy of COVID-19 were searched from the PubMed database. Results Only remdesivir and tocilizumab are medicines that have been approved by the US FDA’s decision to approve their clinical use in moderate and severe COVID-19. Conclusions Favipiravir, ivermectin and andrographolide need further well-conducted research to confirm the efficacy and safety against COVID-19 at different stages.
... Andrographolide is the main active substance of Andrographis paniculate, which can inhibit the proliferation and induce apoptosis of cancer cells [16]. Swati et al. [17] found that it has cytotoxicity to almost all types of cancer cells. At the same time, andrographolide can also be modified by introducing different groups to reduce hydrophobicity and improve bioavailability. ...
Article
Full-text available
In the in-depth research that has been conducted on nanometer biomaterials, how to use the biomass resources with high activity and low toxicity to prepare nanomaterials for biomedical applications has attracted much attention. To realize efficient and comprehensive utilization of biomass, bagasse xylan/andrographolide (BX/AD) was used as a raw material and glycyrrhetinic acid (GA) as an esterification agent to synthesize bagasse xylan/andrographolide esterified derivative (GA-BX/AD). Then, the bagasse xylan/andrographolide grafted and esterified derivative (GA-BX/AD-g-IA) was synthesized by the graft crosslinking reactions using itaconic acid (IA) as graft monomer. The better synthesis conditions were optimized by single factor experiments, the degree of esterification substitution (DS) was 0.43, and the grafting rate (G) of the product reached 42%. The structure and properties of the product were characterized by FTIR, XRD, DTG, SEM, and 1H NMR. The results showed that the product morphology was significantly changed, and the nanoparticles were spherical with a particle size of about 100 nm. The anti-cancer activity of the product was measured. The molecular docking simulations revealed that the product had good docking activity with human glucocorticoid protein (6CFN) with a binding free energy of 14.38 kcal/mol. The MTT assay showed that the product had a strong inhibitory effect on the growth of human liver cancer cells (BEL-7407) and gastric cancer cells (MGC80-3), with inhibition ratio of 38.41 ± 5.32% and 32.69 ± 4.87%. Therefore, this nanomaterial is expected to be applied to the development and utilization of drug carriers and functional materials.
... The present pharmacological evidence points to Andrographis paniculata (Burm. f) Nees (Acanthaceae), a plant that has been commonly used as traditional medicine (Jayakumar et al., 2013;Gupta et al., 2017;Sa-Ngiamsuntorn et al., 2021;Zhang H. et al., 2021), as a promising antiviral candidate for the inhibition of SARS-CoV-2 activity in Thailand. ...
Article
Full-text available
Coronavirus disease 2019 (COVID-19) is a present global health crisis that is driving the investigation of alternative phytomedicines for antiviral purposes. The evidence suggests that Andrographis paniculata crude or extract is a promising candidate for treating symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review aims to consolidate the available reports on the disposition kinetics of andrographolide, a main active component of A. paniculata. The second objective of this review is to summarize the available reports on an appropriate oral dosage for the use of andrographolide in upper respiratory tract infections (URTIs) and other viral infectious diseases. The data were collected from the literature on absorption, distribution, biotransformation, and excretion of andrographolide, and information was also obtained from scientific databases about the use of A. paniculata. The finding of this review on pharmacokinetics indicates that andrographolide is slightly absorbed into the blood circulation and exhibits poor oral bioavailability, whereas its distribution process is unrestricted. In the termination phase, andrographolide preferentially undergoes biotransformation partly through phase I hydroxylation and phase II conjugation, and it is then eliminated via the renal excretion and hepatobiliary system. The key summary of the recommended dosage for andrographolide in uncomplicated URTI treatment is 30 mg/day for children and 60 mg/day for adults. The dose for adult patients with pharyngotonsillitis could be increased to 180 mg/day, but not exceed 360 mg/day. Co-treatment with A. paniculata in concert with the standard supportive care for influenza reduced the severity of symptoms, shortened treatment duration, and decreased the risk of developing post-influenza complications. The recommended starting dose for use in patients with mild COVID-19 is 180 mg/day of andrographolide, based on the dose used in patients experiencing a URTI with inflammation. This review is not only applicable for evaluating the appropriate doses of andrographolide for antiviral treatments but also encourages future research evaluating the effectiveness of these recommended dosages during the COVID-19 pandemic.
... Particularly, Andrographolide paniculata is a medicinal plant found in most Asian countries and has been used in traditional Chinese and Thai medicines [11]. The secondary metabolites of A. paniculata and andrographolide derivatives possess therapeutic properties, such as antiviral, antimicrobial, and anti-parasitic activities, and biological effects including antioxidant and anti-inflammation (reviewed by [12,13]). The main bioactive substances of A. paniculata are diterpenes that contain a γ-lactone ring found in andrographolide (AGL), deoxyandrographolide (DAG), neoandrographolide (NEO), and a few of didehydroandrographolides (DDAG). ...
Article
Full-text available
Foot-and mouth-disease (FMD) caused by the FMD virus (FMDV) is highly contagious and negatively affects livestock worldwide. The control of the disease requires a combination of measures, including vaccination; however, there is no specific treatment available. Several studies have shown that plant-derived products with antiviral properties were effective on viral diseases. Herein, antiviral activities of andrographolide (AGL), deoxyandrographolide (DAG), and neoandrographolide (NEO) against FMDV serotype A were investigated using an in vitro cell-based assay. The results showed that AGL and DAG inhibited FMDV in BHK-21 cells. The inhibitory effects of AGL and DAG were evaluated by RT-qPCR and exhibited EC50 values of 52.18 ± 0.01 µM (SI = 2.23) and 36.47 ± 0.07 µM (SI = 9.22), respectively. The intracellular protease assay revealed that AGL and DAG inhibited FMDV 3Cpro with IC50 of 67.43 ± 0.81 and 25.58 ± 1.41 µM, respectively. Additionally, AGL and DAG significantly interfered with interferon (IFN) antagonist activity of the 3Cpro by derepressing interferon-stimulating gene (ISGs) expression. The molecular docking confirmed that the andrographolides preferentially interacted with the 3Cpro active site. However, NEO had no antiviral effect in any of the assays. Conclusively, AGL and DAG inhibited FMDV serotype A by interacting with the 3Cpro and hindered its protease and IFN antagonist activities.
Article
Glioma is one of the most common malignant primary brain tumors, with poor prognosis and high recurrence. There are currently few drugs approved for brain tumors; thus, it is necessary to develop new effective drugs. Natural diterpenoids have important biological activities, including antiinflammatory, antioxidative, and antitumor effects. In this study, 7α,14β-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione (DGA), a diterpenoid compound modified from glaucocalyxin A, inhibited the proliferation of many tumor cells, especially glioma. Flow cytometry analysis showed that DGA induced apoptosis in glioma cells. DGA also inhibited xenograft tumors in nude mice. It affected the expression of ceramide synthases (CerS) in glioma cells; CerS1 decreased, and CerS2 and CerS5 increased, resulting in a change in the composition of glycosphingolipids containing varying acyl chain lengths. In glioma cells treated with DGA, the gene transcription of activating transcription factor 4 (ATF4), X-box binding protein-1 (XBP1), and C/EBP-homologous protein (CHOP) in unfolded protein response pathways was upregulated. Meanwhile, the ratio of proapoptotic protein Bcl-2–associated X protein (BAX) to antiapoptotic protein B-cell lymphoma 2 (Bcl-2) also increased. This suggested that an imbalance of glycosphingolipids caused by DGA induced severe endoplasmic reticulum stress and triggered cell apoptosis. Moreover, Western blotting showed DGA inhibited the signal transducers and activators of transcription 3 (STAT3) signaling pathway by reducing the phosphorylation of STAT3 and its upstream kinases, which also promoted the apoptosis of glioma cells. Together, these results explored the anticancer activities of DGA and highlighted it as a potential candidate for treating glioma.
Article
Resistant starch (RS) has caught much attention for its potential to exert a beneficial impact on intestine and certain members of its resident microbiota. In this study, we examined how dietary RS promotes intestinal barrier in meat ducks by microbiome-metabolomics analysis. Ducklings were fed corn-soybean basal diet or RS diet. Dietary RS improved intestinal morphology and enhanced barrier function in ileum, evidenced by lower permeability and upregulated tight junction proteins and Mucin-2 gene expression. Microbiome analysis showed that RS administration elevated the proportion of Firmicutes and butyrate-producing bacteria, and increased butyrate contents in cecum. Furthermore, significant alterations in metabolic profiles were observed, with most of these were associated with the amino acid metabolism (especially tryptophan), lipid metabolism, and intestinal inflammation. Together, diet with RS improved gut integrity and caused corresponding alterations in gut metabolome and microbiome, yielding better insights of the mechanism by RS improved the gut system of ducks.
Article
Infection by Zika virus (ZIKV), a mosquito-transmitted arbovirus and a member of Flavivirus, could make pediatric microcephaly and Guillain–Barré syndrome, which remains an ongoing global threat. The efficient antivirals to ZIKV infection are of great medical need. Andrographolide and its analogues were discovered to be active against flaviviral infection. In this study, we discovered some dehydroandrographolide derivatives of 3-oximido- or 3-alcohol-19-hindered ether to be potent anti-ZIKV agents with low cytotoxicities (CC50 > 200 μM). Time of addition assay suggests that compound 5a and its analogues act on inhibition of post-entry stage of ZIKV life cycle. It is discovered by experimental and molecular docking studies that active anti-ZIKV compounds of 3a, 5a, 5b and 5c possess inhibitory activities of ZIKV NS5 MTase (methyl transferase) enzymatic activity. Preliminary SAR reveals that C19-modification with bulky groups is necessary for anti-ZIKV infection and replication, anti-ZIKV activity of 5a comes from itself bearing hindered trityl ether but not from its instability, the backbone of dehydroandrographolide is more effective against ZIKV infection than that of andrographolide, and 3-oxime derivatives are more active against ZIKV infection than 3-alcohol derivatives. To our knowledge, 5a is the first reported MTase inhibitor of andrographolide derivatives. More importantly, discovery of active compound 5b with acid-stable 19-OCHPh2 against ZIKV infection is valued and gives us a clue to design and discover generally acid-stable anti-ZIKV agents.
Article
Full-text available
OBJECTIVE: Epstein-Barr virus (EBV) is a ubiquitous human γ-herpes virus, which can adapt and evade host immune defense. Dendritic cells (DCs) play a pivotal role in the initiation and maintenance of immune responses. This study investigated the effects of EBV on cord blood monocytes derived DCs (CBDC). METHODS: Monocytes were isolated from cord blood and cultured in medium containing recombinant IL-4 and GM-CSF to induce DCs development. B95-8 supernatant was added in monocytes culture medium for EBV infection at day 0. Phenotypic characterization of DCs, apoptotic cells, and mitochondrial membrane potential (MMP) were detected by flow cytometry. The morphology was observed by Hoechst 33258 staining and TUNEL staining, the expression of X-linked inhibitor of apoptosis protein (XIAP) was detected by Western blotting assay and caspase 3, 8 and 9 activity was measured. RESULTS: Phenotypic characterization of DCs was changed in EBV-treated group. Chromatin condensation and DNA fragmentation were observed in EBV induced CBDC apoptosis. In addition, caspase 3, caspase 8, and caspase 9 activation were enhanced in the EBV-treated group. This was accompanied by the loss of MMP. Furthermore, XIAP expression was down-regulated in the EBV-treated group and compared to mock-infected group. CONCLUSION: These results suggested that EBV could inhibit CBDC phenotypic differentiation, and induce CBDC apoptosis in caspase-dependent manner with involvement of the mitochondrial pathway. This might help EBV to evade host immune responses to establish persistent infection.
Article
Full-text available
Andrographis paniculata (Burm. f.) Nees is a medicinal plant which was reported to have anti HIV, anti pathogenic bacteria and immunoregulatory activities. The research purpose was to investigate the activity of Andrographis paniculata ethanol extract as antiviral and immunostimulant. A. paniculata leaves oven-dried, then grinded and macerated with ethanol 90%, and the extract then analyzed using High Performance Liquid Chromatography (HPLC) to determine the content of active compounds andrographolide. The antiviral activity of the extract was determined by observing its ability on inhibiting virus load in A549 cells transfected with Simian Retro Virus (SRV) by Real Time – Polymerase Chain Reaction (RT-PCR) analysis. The immunostimulant activity of extract was determined by its ability to induce lymphocytes cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Our result indicated that the A. paniculata ethanol extract inhibited the SRV virus titer similar to the positive control Lamivudine, and it was not toxic to the A459 cell line. Furthermore, low concentration (1 μg/mL) of A. paniculata extract could stimulated lymphocyte cell proliferation about 38% compared to the control lymphocyte cell without any treatment.
Patent
Full-text available
The present invention provides a methods and compositions for treating a host afflicted with a viral infection, particularly a Flaviviridae infection, including hepatitis C infection, comprising administering an effective antiviral amount of a derivative of andrographolide alone or in combination or alternation with another antiviral compound.
Article
Full-text available
Importance: Human airway secretion contains anti-influenza activity. Different influenza strains may vary in their susceptibility to this antiviral activity. Here we show that the 2009 pandemic and seasonal H1N1 influenza viruses were less sensitive to human bronchoalveolar lavage than H3N2 seasonal influenza virus. The resistance to the pulmonary innate antiviral activity of the pandemic virus was determined by its NA gene and that the NA inhibitor resistant mutation, H275Y, abolished this resistance of the pandemic H1N1 but not the seasonal H1N1 virus, which had compensatory mutations that maintained the fitness of drug resistant strains. Therefore, the innate respiratory tract defense may be a barrier against NA inhibitor resistant mutants and evasion of this defense may play a role in emergence and spreading of drug resistant strains.
Article
The current study investigated the toxic effect of the leaf extract compound andrographolide from Andrographis paniculata (Burm.f) against the dengue vector Ae. aegypti. GC-MS analysis revealed that andrographolide was recognized as the major chemical constituent with the prominent peak area compared with other compounds. All isolated toxic compounds were purified and confirmed through RP-HPLC against chemical standards. The larvicidal assays established at 25 ppm of bioactive compound against the treated instars of Ae. Aegypti showed prominent mortality compared to other treated concentrations. The percent mortality of larvae was directly proportional to concentration. The lethal concentration (LC50) was observed at 12 ppm treatment concentration. The bioactive andrographolide considerably reduced the detoxifying enzyme regulations of alpha- and beta- carboxylesterases. In contrast, the levels of GST and CYP450 significantly increase in a dose dependent manner. The andrographolide also showed strong oviposition deterrence effects at the sub-lethal dose of 12 ppm. Similarly, the mean number of eggs were also significantly reduced in a dose dependent manner. At the concentration of 12 ppm the effective percentage of repellency was greater than 90% with a protection time of 15-210 min, compared with control. The histopathology study displayed that larvae treated with bioactive andrographolide had cytopathic effects in the midgut epithelium compared with the control. The present study established that bioactive andrographolide served as a potential useful for dengue vector management.
Article
The current study investigated the toxic effect of the leaf extract compound andrographolide from Andrographis paniculata (Burm.f) against the dengue vector Ae. aegypti. GC-MS analysis revealed that andrographolide was recognized as the major chemical constituent with the prominent peak area compared with other compounds. All isolated toxic compounds were purified and confirmed through RP-HPLC against chemical standards. The larvicidal assays established at 25 ppm of bioactive compound against the treated instars of Ae. Aegypti showed prominent mortality compared to other treated concentrations. The percent mortality of larvae was directly proportional to concentration. The lethal concentration (LC50) was observed at 12 ppm treatment concentration. The bioactive andrographolide considerably reduced the detoxifying enzyme regulations of α- and β- carboxylesterases. In contrast, the levels of GST and CYP450 significantly increase in a dose dependent manner. The andrographolide also showed strong oviposition deterrence effects at the sub-lethal dose of 12 ppm. Similarly, the mean number of eggs were also significantly reduced in a dose dependent manner. At the concentration of 12 ppm the effective percentage of repellency was greater than 90% with a protection time of 15-210 minutes, compared with control. The histopathology study displayed that larvae treated with bioactive andrographolide had cytopathic effects in the midgut epithelium compared with the control. The present study established that bioactive andrographolide served as a potential useful for dengue vector management.
Article
RIG-I-like receptors detect cytosolic viral RNA and activate an antiviral innate immune response. A new study employs the one STrEP-purification technique and next generation sequencing to characterize physiological ligands in an infected cell. The view of all three RLRs bound to viral RNAs shows specialization, collaboration and new binding sites.
Article
Propolis Extract ACF® (PPE) is a purified extract manufactured from propolis collected in a Canadian region rich in poplar trees, and it is the active substance of a topical ointment used against herpes labialis (cold sores or fever blisters). Aim of this study was to analyze the chemical composition of PPE in order to understand the plant origin and possible relations between compounds and antiviral activity, and to characterize the antiviral activity of the extract against herpes simplex virus in vitro. Material and methods The analysis of the propolis extract samples was conducted by Gas Chromatography–Mass Spectrometry (GC–MS). The antiviral activity was tested against herpes simplex viruses type 1 and type 2 in MDBK cell cultures by treating the cells with PPE at the time of virus adsorption, and by incubating the virus with the extract before infection (virucidal assay). Results Results from the GC–MS analyses revealed a dual plant origin of PPE, with components derived from resins of two different species of poplar. The chemical composition appeared standardized between extract samples and was also reproduced in the sample of topical ointment. The antiviral studies showed that PPE had a pronounced virucidal effect against herpes simplex viruses type 1 and type 2, and also interfered with virus adsorption.