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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.
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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
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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.
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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
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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]
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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
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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.
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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
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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.
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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.
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Andrographolide as an antiviral agent
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... However, their effectiveness, specificity, limitations, and the adverse effects of existing treatments that have occurred in several cases have led to an urgent need for effective drugs for the prevention and treatment of COVID-19. Many studies had previously confirmed the virucidal activity of A. paniculata against different viral strains, including the influenza A virus (IAV), human immunodeficiency virus (HIV), Hepatitis B and C, Herpes Simplex virus I, Epstein-Barr virus, human papillomavirus, and Chikungunya virus [85]. ...
... A. paniculata extract and its bioactive components, as well as the related synthetic compounds, have been studied for their anti-inflammatory activities against endogenous or exogenous causes. Different mechanisms of action were proposed as being responsible for the anti-inflammatory activity of a major compound, andrographoide [24], such as inhibiting intercellular adhesion molecule-1 (ICAM-1) expression and endothelial-monocyte adhesion, induced by tumor necrosis factor-α (TNF) [137], down-regulating the PI3K/Akt signaling pathway, and down-streaming target nuclear factor (NF)-κB activation [138], reducing proinflammatory proteins by blocking the DNA binding of NF-κB [139], suppressing NF-κB and nitric oxide (NO) [85], and modulating macrophage and neutrophil activity [10]. Not only andrographolide but also the diterpenoids isolated from A. paniculata, namely, dehydroandrographolide and neoandrographolide, also exhibited anti-inflammatory activities by affecting cyclooxygenase (COX)-1 and -2 and down-regulating the expression of genes associated with inflammation response, including cytokines and cytokine receptors, chemokines, JAK/STAT signaling, TLRs family, and NF-κB [140]. ...
... Moreover, the crude extract of A. paniculata showed potent inhibitory activities on pro-inflammatory (NO, IL-1 beta, and IL-6) and inflammatory (PGE2 and TXB2) mediators [141]. Several studies have been conducted, suggesting that the anti-inflammatory effect of A. paniculata extract and pure compounds were beneficial in breast, colon, and lung cancer, rheumatoid arthritis, and angiogenesis [85]. The anti-inflammatory properties of andrographolide and the related compounds also suggested protective effects against toxicity in several organs and cells, such as cyclophosphamide (CTX)-induced intestinal toxicity [142], lipopolysaccharideinduced neurotoxicity, and liver and hepatorenal toxicity [10,143]. ...
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The COVID-19 pandemic has intensively disrupted global health, economics, and well-being. Andrographis paniculata (Burm. f.) Nees has been used as a complementary treatment for COVID-19 in several Asian countries. This review aimed to summarize the information available regarding A. paniculata and its constituents, to provide critical points relating to its pharmacological properties, safety, and efficacy, revealing its potential to serve as a source of lead compounds for COVID-19 drug discovery. A. paniculata and its active compounds possess favorable antiviral, anti-inflammatory, immunomodulatory, and antipyretic activities that could be beneficial for COVID-19 treatment. Interestingly, recent in silico and in vitro studies have revealed that the active ingredients in A. paniculata showed promising activities against 3CLpro and its virus-specific target protein, human hACE2 protein; they also inhibit infectious virion production. Moreover, existing publications regarding randomized controlled trials demonstrated that the use of A. paniculata alone or in combination was superior to the placebo in reducing the severity of upper respiratory tract infection (URTI) manifestations, especially as part of early treatment, without serious side effects. Taken together, its chemical and biological properties, especially its antiviral activities against SARS-CoV-2, clinical trials on URTI, and the safety of A. paniculata, as discussed in this review, support the argument that A. paniculata is a promising natural source for drug discovery regarding COVID-19 post-infectious treatment, rather than prophylaxis.
... 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). ...
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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.
... Blocks viral entry into host cells, inhibits viral RNA polymerase, reverse transcriptase, DNA synthesis and immediate-early gene 1(IEG1) transcription, downregulates the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathway [88] Andrographis paniculata (Burm. f.) Nees Fusion and adsorption of virus to the host cell, binding to viral receptor and coreceptor, enzymes involved in the DNA/RNA/Genome replication by the virus, translation, post-translation and reverse transcription [58],enhances cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) [51] Artemisia herba-alba Asso Phytochemicals (4,5-di-O-Caffeoylquinic acid, rutin, and schaftoside) of the plant has binding affinity to SARS-CoV-2 M pro protein complex [55] Artemisia vulgaris L. Induction of cellular ROS, blunting the PI3K/Akt/p70S6K signaling pathway, binding to NF-kB/Sp1 or inducing an endocytosis inhibition mechanism, inhibition of TGF-β signaling [67] Azadirachta indica A. Juss. Blocks virus entry, inhibits viral binding to the cell [106], interacts with SARS-CoV-2 membrane (M) and envelope (E) protein [28] Camellia sinensis (L.) Kuntze Inhibits viral RNA replication, erythrocyte agglutination; blocks viral entry into hose cells; downregulates RNA synthesis; interferes core promoter transcription, virus absorption; prevents cell to cell transmission; disrupts viral membrane integrity; and reduces Nf-kB expression [119] Citrus limon (L.) Osbeck Hepatitis A virus titer was reduced by 2.84 log TCID50/ml after treatment with citrus lemon EO at 0.5% [20] Curcuma longa L. Inhibits SARS-CoV 3CL protease, hemagglutinin, viral RNA replication, viral assembly, virus binding to host cell; disrupts viral membrane proteins [104] Eucalyptus globulus Labill. ...
Article
Background: Since the outbreak of the COVID-19 virus, ethnomedicinal plants have been used in diverse geographical locations for their purported prophylactic and pharmacological effects. Medicinal plants have been relied on by people around the globe for centuries, as 80% of the world’s population rely on herbal medicines for some aspect of their primary health care needs, according to the World Health Organization. Main body: This review portrays advances in traditional phytomedicine by bridging the knowledge of ethno-phytomedicine and COVID-19 healthcare. Ethnomedicinal plants have been used for symptoms related to COVID-19 as antiviral, anti-infective, anti-inflammatory, anti-oxidant, antipyretic, and lung–gut immune boosters. Traditionally used medicinal plants have the ability to inhibit virus entry and viral assembly, bind to spike proteins, membrane proteins, and block viral replications and enzymes. The efficacy of traditional medicinal plants in the terms of COVID-19 management can be evaluated by in vitro, in vivo as well as different in silico techniques (molecular docking, molecular dynamics simulations, machine learning, etc.) which have been applied extensively to the quest and design of effective biotherapeutics rapidly. Other advances in traditional phytomedicines against COVID-19 are controlled clinical trials, and notably the roles in the gut microbiome. Targeting the gut microbiome via medicinal plants as prebiotics is also found to be an alternative and potential strategy in the search for a COVID-19 combat strategy. Conclusions: Since medicinal plants are the sources of modern biotherapeutics development, it is essential to build collaborations among ethnobotanists, scientists, and technologists toward developing the most efficient and the safest adjuvant therapeutics against the pandemic of the twenty-first century, COVID-19.
... Recently, andrographolide has been shown to also inhibit the AIM2 inflammasome by preventing AIM2 from translocating into the nucleus to sense DNA damage during the development of radiation fibrosis in BMDM cells (Gao et al., 2019). Andrographolide has been investigated in several diseases, however, due to its effects on AIM2 it is been closely investigated for its antiviral properties (Gupta et al., 2017;Reshi and Chi-Yong, 2020;Shi et al., 2020). ...
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The NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18. NLRP3 is the most extensively studied inflammasome to date due to its array of activators and aberrant activation in several inflammatory diseases. Studies using small molecules and biologics targeting the NLRP3 inflammasome pathway have shown positive outcomes in treating various disease pathologies by blocking chronic inflammation. In this review, we discuss the recent advances in understanding the NLRP3 mechanism, its role in disease pathology, and provide a broad review of therapeutics discovered to target the NLRP3 pathway and their challenges.
... The ent-labdane andrographolide (Fig. 1B) isolated from the ''King of Bitters" plant Andrographis paniculata is one of the prominent natural products that has been attracted attention in recent years. It has been shown to exert a wide range of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, hepatoprotective and particularly antiviral effects [21][22][23][24]. A. paniculata extract is traditionally used to alleviate common cold symptoms, fever and diarrhea, as well as upper respiratory and inflammatory diseases [25]. The clinical trials show that there are no serious adverse effects observed in patients [26,27]. ...
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A global crisis of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted millions of people’s lives throughout the world. In parallel to vaccine development, identifying potential antiviral agents against SARS-CoV-2 has become an urgent need to combat COVID-19. One of the most attractive drug targets for discovering anti-SARS-CoV-2 agents is the main protease (Mpro), which plays a pivotal role in the viral life cycle. This study aimed to elucidate a series of twenty-one 12-dithiocarbamate-14-deoxyandrographolide analogues as SARS-CoV-2 Mpro inhibitors using in vitro and in silico studies. These compounds were initially screened for the inhibitory activity toward SARS-CoV-2 Mpro by in vitro enzyme-based assay. We found that compounds 3k, 3l, 3m and 3t showed promising inhibitory activity against SARS-CoV-2 Mpro with >50% inhibition at 10 μM. Afterward, the binding mode of each compound in the active site of SARS-CoV-2 Mpro was explored by molecular docking. The optimum docked complexes were then chosen and subjected to molecular dynamic (MD) simulations. The MD results suggested that all studied complexes were stable along the simulation time, and most of the compounds could fit well with the SARS-CoV-2 Mpro active site, particularly at S1, S2 and S4 subsites. The per-residue decomposition free energy calculations indicated that the hot-spot residues essential for ligand binding were T25, H41, C44, S46, M49, C145, H163, M165, E166, L167, D187, R188, Q189 and T190. Therefore, the obtained information from the combined experimental and computational techniques could lead to further optimization of more specific and potent andrographolide analogues toward SARS-CoV-2 Mpro.
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This review presents information from several studies that have demonstrated the antiviral activity of extracts ( Andrographis paniculata, Artemisia annua, Artemisia afra, Cannabis sativa, Curcuma longa, Echinacea purpurea, Olea europaea, Piper nigrum, and Punica granatum) and phytocompounds derived from medicinal plants (artemisinins, glycyrrhizin, and phenolic compounds) against SARS-CoV-2. A brief background of the plant products studied, the methodology used to evaluate the antiviral activity, the main findings from the research, and the possible mechanisms of action are presented. These plant products have been shown to impede the adsorption of SARS-CoV-2 to the host cell, and prevent multiplication of the virus post its entry into the host cell. In addition to antiviral activity, the plant products have also been demonstrated to exert an immunomodulatory effect by controlling the excessive release of cytokines, which is commonly associated with SARS-CoV-2 infections.
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A late-stage functionalization (LSF) of the natural product andrographolide for the efficient assembly of a range of structurally interesting and diverse tricyclic-aza derivatives was developed. The key to the diversification is a photo-catalyzed intramolecular hydroamination reaction, and acridinium derivatives were demonstrated to be the optimal catalysts. Additionally, the synthesized tricyclic aza-andrographolide derivatives were found to inhibit human coronavirus with high potency.
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ISGylation is an important process through which interferon-stimulated genes (ISGs) elicit an antiviral response in the host cells. Several viruses, including the SARS-CoV-2, suppress the host immune response by reversing the ISGylation through a process known as de-ISGylation. The PLpro of SARS-CoV-2 interacts with the host ISG15 and brings about de-ISGylation. Hence, inhibiting the de-ISGylation to restore the activity of ISGs can be an attractive strategy to augment the host immune response against SARS-CoV-2. In the present study, we evaluated several phytochemicals from well-known immunomodulatory herbs, viz. Andrographispaniculata (AG), Tinospora cordifolia (GU), and Ocimum sanctum (TU) for their effect on deISGylation that was mediated by the PLpro of SARS-CoV2. For this purpose, we considered the complex 6XA9, which represents the interaction between SARS-CoV-2 PLpro and ISG15 proteins. The phytochemicals from these herbs were first evaluated for their ability to bind to the interface region between PLpro and ISG15. Molecular docking studies indicated that 14-deoxy-15-isopropylidene-11,12-didehydroandrographolide (AG1), Isocolumbin (GU1), and Orientin (TU1) from AG, GU, and TU, respectively possess better binding energy. The molecular dynamic parameters and MMPBSA calculations indicated that AG1, GU1, and TU1 could favorably bind to the interface and engaged key residues between (PLpro-ISG15)-complex. Protein–protein MMPBSA calculations indicated that GU1 and TU1 could disrupt the interactions between ISG15 and PLpro. Our studies provide a novel molecular basis for the immunomodulatory action of these phytochemicals and open up new strategies to evaluate drug molecules for their effect on de-ISGylation to overcome the virus-mediated immune suppression.
Chapter
Angiotensin-converting enzyme (ACE) inhibitors are used to control blood pressure or to prevent congestive heart failure by dilating blood vessel. These inhibitors are also applied to treat patients with kidney injury or diabetic nephropathy. Due to the side effects of the synthetic drugs, such as dizziness, hyperkalemia, angioedema, dysgeusia and renal impairment, there is an increasing trend in using natural products, especially bioactive peptides and polysaccharides, that can be extracted from various plants, animals or microorganisms, in which much lower cytotoxicity was detected. In this chapter, we have gathered the most recent data and reviewed it for these two active components in the aspect of sources, extraction/identification techniques and mechanism in inhibiting ACE, as well as the commercialization potential including the effectiveness after the oral consumption.
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Proteases play a key role in the pathogenesis of RNA viruses. They modify viral polypeptides by proteolytic cleavage post translation. Proteases are the potential targets for the treatment of viral diseases. Since December 2019, the world has observed the emergence of SARS-CoV-2 that resulted in Covid-19 pandemic and brought the world to a stand-still. It exposed the limitations of medical facilities and medicines to treat Covid-19. The search for vaccines and drugs against SARS-CoV-2 became the major task of the scientific community. The thrust area of research was the search for an inhibitor of protease Mpro (also known as the main protease) of SARS-CoV-2. The search for new molecules and their in vitro trials is time consuming. Therefore, the in silico approaches such as structure and ligand-based virtual screening, docking and molecular dynamics were extensively used to search for the promising inhibitor of Mpro from the existing library of natural molecules. The present review summarizes the potential inhibitors of Mpro from the natural sources such as plants, metabolites from microorganisms including marine algae.
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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.
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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.
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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.
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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.
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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.
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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.