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In vitro Inhibition of Zika Virus by Metadichol®, A Novel Nano Emulsion Lipid

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In vitro Inhibition of Zika Virus by Metadichol®, A Novel Nano Emulsion Lipid

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Abstract Objective: To show the antiviral activity of Metadichol® against Zika virus by an in-vitro assay. Methods: The primary Anti-Zika virus assay was performed using real-time RT-qPCR (TaqMan) to measure extracellular Zika virus RNA copy number associated with virions released from vero cells. The ‘vero’ cell line (kidney epithelial cells extracted from an African green monkey) treated with antiviral test articles is infected with Zika virus followed by Zika virus associated RNA measurement in the cell culture supernatant. Antiviral compounds blocking any step of viral replication such as transcription, translation, encapsidation, the particle assembly and release were identified and characterized using this sensitive assay system. Findings: Metadichol® (1-2) in vitro assays,( inhibited the Zika Virus with a EC50 of 1.48 μg/ml. Conclusion: Metadichol is a safe and effective inhibitor for enveloped viruses in humans. Since it is known to bind to the vitamin D receptor (VDR), its action mechanism likely involves the competitive displacement of virus particles from VDR’s on host cell membranes. Metabolism studies of long chain alcohol in fibroblasts suggest that very long chain fatty alcohols, fatty aldehydes, and fatty acids are reversibly interconverted in a fatty alcohol cycle [3]. Metadichol consists of natural components of common foods (classified as GRAS), Metadichol has no known negative side effects. The inhibition of Zika virus by Metadichol is not surprising, given that we have recently published the results of Metadichol which showed broad-spectrum antiviral activity against Dengue, Ebola, H1N1, SARS, Chikungunya and other enveloped viruses.(4)
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a SciTechnol journal
Raghavan, J Immunol Tech Infect Dis 2016, 5:4
DOI: 10.4172/2329-9541.1000151
All articles published in Journal of Immunological Techniques in Infectious Diseases are the property of SciTechnol, and is
protected by copyright laws. Copyright © 2016, SciTechnol, All Rights Reserved.
Journal of Immunological
Techniques in Infectious Diseases
International Publisher of Science,
Technology and Medicine
Research Article
In vitro Inhibition of Zika Virus
by Metadichol®, A Novel Nano
Emulsion Lipid
Raghavan PR*
Abstract
Objective: To show the antiviral activity of Metadichol® against Zika
virus by an in-vitro assay.
Methods: The primary Anti-Zika virus assay was performed using
real-time RT-qPCR (TaqMan) to measure extracellular Zika virus
RNA copy number associated with virions released from vero cells.
The ‘vero’ cell line (kidney epithelial cells extracted from an African
green monkey) treated with antiviral test articles is infected with
Zika virus followed by Zika virus associated RNA measurement in
the cell culture supernatant. Antiviral compounds blocking any step
of viral replication such as transcription, translation, encapsidation,
the particle assembly and release were identied and characterized
using this sensitive assay system.
Findings: Metadichol® (1-2) in vitro assays,( inhibited the Zika
Virus with a EC50 of 1.48 µg/ml.
Conclusion: Metadichol is a safe and effective inhibitor
for enveloped viruses in humans. Since it is known to bind to
the vitamin D receptor (VDR), its action mechanism likely
involves the competitive displacement of virus particles from
VDR’s on host cell membranes. Metabolism studies of long
chain alcohol in fibroblasts suggest that very long chain fatty
alcohols, fatty aldehydes, and fatty acids are reversibly
interconverted in a fatty alcohol cycle [3]. Metadichol consists
of natural components of common foods (classified as GRAS),
Metadichol has no known negative side effects. The inhibition of
Zika virus by Metadichol is not surprising, given that we have
recently published the results of Metadichol which showed
broad-spectrum antiviral activity against Dengue, Ebola,
H1N1, SARS, Chikungunya and other enveloped viruses.(4)
Keywords
Zika; Ebola; Dengue; Chikungunya; H1N1; Respiratory viruses;
Metadichol; VDR; Inverse agonist; Protean agonist
*Corresponding author: PR Raghavan, Founder and CEO, Nanorx Inc., PO
Box 131, Chappaqua, NY 10514, USA, E-mail: raghavan@nanorxinc.com
Received: October 05, 2016 Accepted: November 02, 2016 Published:
November 07, 2016
In February 2016, the WHO [5] asserted that the potential
association between Zika and microcephaly constitutes an
international public health emergency.
Mosquito-born Zika virus and complications associated with the
transmission of the virus has been at the forefront of much public
discussion. e epidemic of Zika virus (ZIKV) infection was reported
in 2015 in South and Central America and the Caribbean. A major
concern associated with this infection is the apparent increased
incidence of microcephaly in fetuses born to the mothers infected
with ZIKV. e potential congenital problems associated with the
contracting Zika during pregnancy as well as the risk for serious
autoimmune and neurological problems in aected subjects is being
highlighted [6].
e family Flaviviridae contains some of the most clinically
important arboviruses. is genus includes viruses like the West
Nile, Dengue, tick borne encephalitis, Yellow fever, Zika and several
other viruses which may cause encephalitis. Flaviviruses share several
common aspects, such as common size (40-65 nm), symmetry
(enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense,
single-stranded RNA around 10,000-11,000 bases). Most of these
viruses are transmitted by an infected mosquito bite or tick and
hence, classied as arboviruses [7].
Enveloped viruses are then free to begin a new cycle of infection
by fusing their cell-derived envelope with the cellular membrane of
an uninfected cell. Some types of enveloped virus fuse directly to the
cell’s outer (plasma) membrane, whereas others are engulfed wholly
by endocytosis or similar process and then fuse their envelope with the
membrane of the engulfed internal organelle (e.g., endosome) to gain
access to the interior of the cell. In either case, the genetic material
of the virus invades the cell through the barrier of its membrane,
and infection follows inevitably. e most reliable way to prevent
infection caused by any virus is to eliminate it’s entry in the rst
place. All available antiviral therapeutic compounds block replication
processes shared by the virus and infected target cells [8]. Such
compounds are thus potentially toxic, mutagenic, and teratogenic for
the host and can induce drug-resistant for viral mutant sub-strains.
Consequently, identication of ecacious new antiviral compounds
that lack such deleterious eects is very important.
Metadichol is a nanoemulsion of long-chain alcohols found in
many foods. It’s active ingredients are commonly called Policosanols.
It is present in many foods such as rice, sugar cane, wheat, peanuts
[3]. Metadichol acts on Nuclear Vitamin D receptor (VDR) [2] in
cells throughout the body to stimulate the immune system and inhibit
a variety of disease processes, including those resulting from viral
infections [9].
We had previously documented two patients diagnosed with
dengue fever in SE Asia [4] who were volunteered to be treated
with Metadichol®. Based on the positive outcome, we then tested for
antiviral activity of Metadichol® in vero and MDCK cells infected
with Dengue, Ebola, Marburg, Inuenza A ( H1N1), C hikungunya
and Human Respiratory Syncytial viruses. In addition, we tested
the ecacy of Metadichol® in preventing the cell death caused by
Adenovirus, Tacaribe Mammarenavirus, Ri Valley Fever virus, SARS
coronavirus, Japanese Encephalitis virus, West Nile virus, and Yellow
Introduction
So oen, news about a viral outbreak goes viral that makes news
headline. Human immunodeciency virus (HIV), West Nile virus,
avian inuenza (bird u), Ebola, Middle East respiratory virus,
and Zika virus, each of these have become the focus of the media’s
spotlight. eir views leave the public with a new health concern to
worry about but little knowledge about the actual factors is involved
in the problem.
Citation: Raghavan PR (2016) In vitro Inhibition of Zika Virus by Metadichol®, A Novel Nano Emulsion Lipid. J Immunol Tech Infect Dis 5:4.
Page 2 of 6
doi: 10.4172/2329-9541.1000151
Volume 5 • Issue 4 • 1000151
Fever virus (Figure 1). At that time, there was no assay available for
Zika. Recently, it became widely available and Metadichol was tested
against the Zika Virus.
As shown previously [4], Metadichol® exhibit potent, broad
spectrum viral inhibitory activity and it’s lack of toxic, mutagenic, or
teratogenic properties has been well documented [10,11,12].
Experimental
e in-vitro assay was outsourced on commercial contract basis
to Southern Research and the assay was carried out at their Infectious
Disease Research Facility in Frederick, Maryland, USA. Vero cells
were plated in 96-well micro titer plates at 1×104 cells/well in Dulbecco’s
Modied Eagle’s Medium supplemented with 2% FBS, 2.0 mM
L-Glutamine, 100 units/mL Penicillin, 100 µg/mL Streptomycin, and
0.1 mM non-essential amino acids. e interior was utilized to reduce
“edge eects” observed during cell culture; the exterior wells were
lled with complete medium to help minimize sample evaporation.
Aer 16-24 hours the conuent monolayer of vero cells were washed
and the medium was replaced with complete medium containing
various concentrations of the test compound in triplicate (Table 1)
for a representative plate layout for testing compounds at six half-log
concentration), followed by infection with Zika virus. Interferon alpha
(IFNα) was used as the positive control, while media alone was added
to cells as a negative control (virus control, VC). ree days followed
by the initial administration of the test compound, the cell culture
supernatant was used in a real-time quantitative TaqMan qPCR assay.
e RT-PCR-amplied Zika viral RNA was detected in real-time by
monitoring the increase in uorescent signal that resulted from the Exo-
nucleolytic degradation of a quenched uorescent probe molecule that
hybridized to the amplied Zika RNA. For each PCR amplication, a
standard curve is simultaneously generated using dilutions of puried
Zika viral RNA. Antiviral activity was calculated from the reduction in
Zika viral RNA levels (EC50 & EC90 values determined). A tetrazolium
dye (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-
sulfophenyl)-2H-tetrazolium; Cell Titer®96 Reagent, Promega) uptake
assay was then employed to measure cell viability using the same assay
plate, and the viability data was used to calculate compound cytotoxicity
(CC50). e Selectivity Index (SI50) was calculated as CC50/EC50.
Results of In-Vitro Antiviral Activity
Shown in Tables 1-4 and Figures 1-3.
Discussion
Metadichol against Zika virus showed an EC 50 of 1.48 µg/ml and
EC90 of 5.01 µml. ese results were in line with the EC50 of 8·75 μg/mL
and 3·96 μg/mL as we previously reported [4] against Ebola (Mayinga)
and Marburg virus (Musoke), respectively. e EC50 of Metadichol
against DENV-2 (New Guinea C), CHIKV (181/25), and HRSV (A2)
was 2·91 μg/mL, 3·54 μg/mL, and 0·41 μg/mL, respectively. e EC50
of Metadichol against Inuenza A (CA/07/09) was 5·44 μg/mL.
Previous studies have demonstrated the antiviral activities
of moderate-length saturated and unsaturated alcohols at mM
concentrations [13,14]. Optimal antiviral activity was observed with
saturated alcohols 10 to 12 carbons long; however, those compounds
Figure 1: Summary of Metadichol EC50 values against viruses.
Citation: Raghavan PR (2016) In vitro Inhibition of Zika Virus by Metadichol®, A Novel Nano Emulsion Lipid. J Immunol Tech Infect Dis 5:4.
Page 3 of 6
doi: 10.4172/2329-9541.1000151
Volume 5 • Issue 4 • 1000151
also exhibited cytotoxic and hemolytic eects. Less antiviral activity
was observed with alcohols 14 to 18 carbons long; alcohols with longer
chain lengths were not tested. Katz [15] showed that compositions
of one or more aliphatic alcohols containing 27 to 32 carbons were
suitable for intravenous or intramuscular injection into humans or
mammals.
Nutritional status might exert a profound eect on immune
system functions. Hence, several parameters of immune system
are modied by dietary lipid administration, such as lymphocyte
proliferation, cytokine production, natural killer activity, antigen
presentation, etc. us, numerous studies have indicated the key role
of lipids as immune response modulators. ese properties have been
applied in the treatment of autoimmune and inammatory diseases
[16].
Metadichol is a nanoemulsion of long-chain lipid alcohols (C-
26, C-28 and C-30), which are commonly known as Policosanols.
Metabolism studies in broblasts suggest that very long chain fatty
alcohols, fatty aldehydes, and fatty acids are reversibly interconverted
in a fatty alcohol cycle [17,18]. Since the metabolites of long chain
alcohols are interconverted, a single dosage even at low doses can
theoretically have lasting eects. Metadichol has a particle size of less
than 60 nm. We have shown that it binds to the vitamin D receptor
(VDR) as an inverse agonist. It is the only known inverse agonist of
VDR found in medical literature [2].
Calcitriol (1,25-Dihydroxy Vitamin D) is the natural ligand for
the VDR and act as an agonist. Metadichol likely behaves more like
a protean agonist.Protean agonists act as both positive and negative
agonists on the same receptor, depending on the degree of presence
of constitutive activity. If there is no constitutive activity, the agonist
would be a positive agonist. When constitutive activity is present, the
protean agonist would be an inverse agonist [19].
Vitamin D is essential to the skeletal system [9,20,21] and recent
evidence suggested that it also play a major role in regulating the
immune system, perhaps through the involvement in immune
responses to viral infections [22]. Cell culture experiments supported
the hypothesis that vitamin D has direct antiviral eects, particularly
against enveloped viruses. e antiviral mechanism of vitamin D may
be due to the ability of vitamin D to up regulate the antimicrobial
peptides LL-37 (cathelicidin) and human beta-defensin. Human
cathelicidin has been shown to aect several viruses including VV,
RSV, inuenza virus, HIV, HSV, DENV and Adenovirus via virus
envelope disruption, and polymerase or protease inhibition [23].
Viruses have evolved strategies to exploit the VDR and other
receptors to regulate the expression of their genes and to optimize the
cellular processes intrinsic to the viral life cycle. PersistentEpstein-
Barr virus infection down regulates VDR >10 fold [24,25]. While
the specic receptors targeted by viruses vary and involve processes
that directly or indirectly modulate receptor function. e specic
receptor(s) targeted by a particular virus are likely to reect the tissue
tropism of the virus. By binding to the VDR (which is a key receptor
for innate immunity and is present in all cells), Metadichol can
displace viruses bound to it and block viral entry into the host cells.
e fact that Metadichol has inhibitory eects against many viruses
suggests that viral binding to the VDR does occur and that Metadichol
competitively disrupts this process. In addition to VDR binding,
Metadichol shares cross-reactivity with other nuclear receptors [26],
which may explain its activity against a wide range of viruses.
Conclusion
Metadichol constituents are long-chain lipid alcohols which are
classied as GRAS, and present in foods that are consumed on a daily
basis. Metadichol has demonstrated no toxicity at doses of up to 5000
mg/kg [10,11,12] and is a renewable resource.
1 2 3 4 5 6 7 8 9 10 11 12
A Media Media Media Media Media Media Media Media Media Media Media Media
B Media Cells + Drug
1 100 uM
Cells + Drug
1 100 uM
Cells + Drug
1 100uM
Cells + Drug
2 100 uM
Cells +
Drug 2
100uM
Cells + Drug 2
100uM
Cells + Drug
3 100uM
Cells + Drug
3 100 uM
Cells + Drug 3
100 uMVC Media
C Media
Cells + Drug
1
32 uM
Cells + Drug
1
32 uM
Cells + Drug
1
32 uM
Cells + Drug
2
32 uM
Cells +
Drug 2
32 uM
Cells + Drug 2
32 uM
Cells + Drug
3
32 uM
Cells + Drug
3
32 uM
Cells + Drug 3
32 uMVC Media
D Media
Cells + Drug
1
10 uM
Cells + Drug
1
10 UM
Cells + Drug
1
10 uM
Cells + Drug
2
10 uM
Cells +
Drug 2
10 uM
Cells + Drug 2
10 uM
Cells + Drug
3
10 uM
Cells + Drug
3
10 uM
Cells + Drug 3
10 uMVC Media
E Media
Cells + Drug
1
3.2 uM
Cells + Drug
1
3.2 uM
Cells + Drug
1
3.2 uM
Cells + Drug
2
3.2 uM
Cells +
Drug 2
3.2 uM
Cells + Drug 2
3.2 uM
Cells + Drug
3
3.2 uM
Cells + Drug
3
3.2 uM
Cells + Drug 3
3.2 uMVC Media
F Media
Cells + Drug
1
1 uM
Cells + Drug
1
1 uM
Cells + Drug
1
1 uM
Cells + Drug
2
1 uM
Cells +
Drug 2
1 uM
Cells + Drug 2
1 uM
Cells + Drug
3
1 uM
Cells + Drug
3
1 uM
Cells + Drug 3
1 uMVC Media
GMedia
Cells + Drug
1
320nM
Cells + Drug
1
320nM
Cells + Drug
1
320nM
Cells + Drug
2
320nM
Cells +
Drug 2
320nM
Cells + Drug 2
320nM
Cells + Drug
3
320nM
Cells + Drug
3
320nM
Cells + Drug 3
320nM VC Media
H Media Media Media Media Media Media Media Media Media Media Media Media
Table 1: Illustrative example of a plate layout, 96-Well Tissue Culture Plate Format for Zika virus Drug Screening; VC = Virus control, which is the Vero cells alone
without compound.
Compound Concentration Units EC90 EC50 CC50
Selectivity Index
(CC50/EC50)
Metadichol µg/mL 5.01 1.48 4.25 2.87
IFN-alpha IU/mL 27.2 <3.16 >1000 >316
Table 2: In-vitro Anti-Zika Evaluation: Raw Data and Summary Graph for Metadichol vs Zika Virus.
Citation: Raghavan PR (2016) In vitro Inhibition of Zika Virus by Metadichol®, A Novel Nano Emulsion Lipid. J Immunol Tech Infect Dis 5:4.
Page 4 of 6
doi: 10.4172/2329-9541.1000151
Volume 5 • Issue 4 • 1000151
LOCATION ON
PLATE CONC(µG/ML)
ANTIVIRAL TEST VALUES CYTOTOXICITY TEST VALUES
MEAN ZIKA
RNA
%CONTROL ZIKA
RNA
SD ZIKA
RNA % %CV MEAN
Cytotox
% CONTROL VI-
ABILITY SD Cytotox % CV
B2-G2
B3-B5
C3-C5
D3-D5
E3-E5
F3-F5
G3-G5
CONTROL
0.079
0.25
0.79
2.50
7.91
25.0
1118459
1029493
10966952
905626
273262
5546
4226
100%
92%
98%
81%
24%
0%
0%
206630
344895
899504
95733
225308
1658
664
18.5%
30.8%
80.4%
8.6%
20.1%
0.1%
0.1%
0.9212
0.8927
0.8580
0.8642
0.8229
0.0366
0.0175
100%
97%
93%
94%
89%
4%
2%
0.0589
0.0107
0.353
0.0770
0.0369
0.0361
0.0029
6.4%
1.2%
3.8%
8.4%
4.0%
3.9%
0.3%
Table 3: Raw Data: Metadichol Vs. Zika Virus.
1 2 3 4 5 6 7 8 9 10 11 12
A
Media
Media
Media
CC drug experimental
B 0.8623 0.9003 0.8852
C 1.0058 0.8330 0.8829
D 0.9743 0.8098 0.9187
E 0.9293 0.7968 0.8490
F 0.8837 0.0622 0.0111
G0.8719 0.0154 0.0195
H Media
Metadichol and its Cytotoxicity data (O.D.) and efcacy data (copies of Zika RNA)
RAW DATA
CYTOTOXICITY DATA (O.D):
CC=Cell control BOLD-highest drug concentration
EFFICACY DATA (COPIES OF ZIKA RNA):
1 2 3 4 5 6 7 8 9 10 11 12
A
Media
Media
Media
VC drug experimental
B 906836 785616 1273371
C 1083625 460907 1732998
D 1364918 973320 837933
E 906836 113945 432579
F 1083623 4373 6718
G1364918 3756 4695
H Media
VC=Virus control BOLD-highest drug concentration
LOCATION ON
PLATE CONC(µG/ML)
ANTIVIRAL TEST VALUES CYTOTOXICITY TEST VALUES
MEAN ZIKA
RNA
%CONTROL ZIKA
RNA
SD ZIKA
RNA %CV MEAN
Cytotox
% CONTROL VI-
ABILITY SD Cytotox % CV
B2-G2
B6-B8
C6-C8
D6-D8
E6-E8
F6-F8
G6-G8
CONTROL
3.16
9.99
31.6
99.9
316
1,000
1118459
371155
227176
94763
86443
4793
1421
100%
33%
20%
8%
8%
0%
0%
206630
101695
91634
77641
26033
1881
1009
18.5%
9.1%
8.2%
6.9%
2.3%
0.2%
0.1%
0.9212
0.9037
0.8885
0.9277
0.9478
0.9485
1.0556
100%
98%
96%
101%
103%
103%
115%
0.0589
0.0021
0.0116
0.0206
0.0216
0.0607
0.0168
6.4%
0.2%
1.3%
2.2%
2.3%
6.6%
1.8%
Table 4: Raw Data IFN-alpha vs Zika Virus.
IFN-alpha and its Cytotoxicity data (O.D.) and efcacy data (copies of Zika RNA)
RAW DATA
CYTOTOXICITY DATA (O.D):
1 2 3 4 5 6 7 8 9 10 11 12
A
Media
Media
Media
CC drug experimental
B 0.8623 0.9023 0.9052
C 1.0058 0.8803 0.8067
D 0.9743 0.9131 0.9423
E 0.9293 0.9326 0.9631
F 0.8837 0.9055 0.9914
G0.8719 1.0675 1.0437
H Media
VC=Virus control BOLD-highest drug concentration
Citation: Raghavan PR (2016) In vitro Inhibition of Zika Virus by Metadichol®, A Novel Nano Emulsion Lipid. J Immunol Tech Infect Dis 5:4.
Page 5 of 6
doi: 10.4172/2329-9541.1000151
Volume 5 • Issue 4 • 1000151
EFFICACY DATA (COPIES OF ZIKA RNA):
1 2 3 4 5 6 7 8 9 10 11 12
A
Media
Media
Media
VC drug experimental
B 906836 443064 299245
C 1083625 162381 291791
D 1364918 149664 39362
E 906836 68035 104852
F 1083623 6123 3463
G1364918 707 2134
H Media
VC=Virus control BOLD-highest drug concentration
Figure 2: Summary graph for Metadichol versus Zika Virus.
Drug: Metadichol
Virus: Zika MR 766
Cells: VERO
Figure 3: In-vitro Anti-Zika Evaluation:
Drug: IFN-alpha
Virus: Zika MR 766
Cells:VERO
Citation: Raghavan PR (2016) In vitro Inhibition of Zika Virus by Metadichol®, A Novel Nano Emulsion Lipid. J Immunol Tech Infect Dis 5:4.
Page 6 of 6
doi: 10.4172/2329-9541.1000151
Volume 5 • Issue 4 • 1000151
Metadichol could serve as a preventive agent for Zika given
that it strengthens the innate immunity through VDR binding, and
represent the rst key step in preventing diseases. Metadichol is ready
for large scale testing in areas which are ravaged by viruses. Once
proven on large populations, Metadichol could be used as a preventive
nutritional supplement in countries where viral fevers are widely
prevalent. Metadichol is being sold as a nutritional supplement in a few
Asian countries for the last two years and is extremely well tolerated. So
far, there have been no reports of any adverse side eects.
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... Metadichol ® is a nano lipid formulation of long-chain alcohols 14 . Metadichol has been shown to inhibit viruses in vitro and in vivo [15][16][17] . Metadichol was tested for its inhibitory actions against ACE2 and TMPRSS2 and in an antiviral assay with SARS-COV-2. ...
... Comparatively, this result indicates that Metadichol has a 2000fold higher effectiveness than Remdesivir and 4000-fold potency over hydroxychloroquine phosphate 18. . A previously published work 15 of antiviral data against other viruses is shown in Tables 3 and 4. Raw data show the cytotoxicity of Metadichol without a virus present in Vero cells was measured by neutral red assay. When >75% "toxicity" occurred in the absence of virus, no viral CPE value was reported. ...
Preprint
Full-text available
New pathogenic virus outbreaks, occurring with increasing regularity, are leading us to explore novel approaches, which will reduce the reliance on time-consuming vaccine modes to halt the outbreaks. The requirement is to find a universal approach to disarm any new and as yet unknown viruses as they appear. A promising approach could be targeting lipid membranes, which are common to all viruses and bacteria. The ongoing pandemic of severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2) has reaffirmed the importance of interactions between components of the host cell plasma membrane and the virus envelope as a critical mechanism of infection. Metadichol®, a nano lipid emulsion, has been examined and shown to be a strong candidate to help stop the proliferation of SARS-COV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce the infectivity of various types of viruses, including coronaviruses such as SARS-COV-2, by modifying lipid-dependent attachment to human host cells. SARS-COV-2 uses the receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. Metadichol®, a nano lipid formulation of long-chain alcohols, has been shown to inhibit TMPRSS2 (EC50 96 ng/ml). Compared to the inhibitor camostat mesylate (EC50 26000 ng/ml), it is 270 times more potent. Additionally, Metadichol® is also a extremely weak inhibitor of ACE2 at 31 µg/ml. Further a live virus assay in Caco2 cells, Metadichol® inhibited SARS-CoV-2 replication with an EC90 of 0.16 µg/ml.
... Metadichol ® is a nano lipid formulation of long-chain alcohols [14]. Metadichol has been shown to inhibit viruses in vitro and in vivo [15][16][17]. Metadichol was tested for its inhibitory actions against ACE2 and TMPRSS2 and in an antiviral assay with SARS-COV-2. ...
... A previously published work [15] of antiviral data against other viruses is shown in Tables 3 and 4. Raw data ...
Preprint
Full-text available
Background New pathogenic virus outbreaks, occurring with increasing regularity, are leading us to explore novel approaches, which will reduce the reliance on time-consuming vaccine modes to halt the outbreaks. The requirement is to find a universal approach to disarm any new and as yet unknown viruses as they appear. A promising approach could be targeting lipid membranes, which are common to all viruses and bacteria.The ongoing pandemic of severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2) has reaffirmed the importance of interactions between components of the host cell plasma membrane and the virus envelope as a critical mechanism of infection. Metadichol®, a nano lipid emulsion, has been examined and shown to be a strong candidate to help stop the proliferation of SARS-COV-2.Naturally derived substances, such as long-chain saturated lipid alcohols, reduce the infectivity of various types of viruses, including coronaviruses such as SARS-COV-2, by modifying lipid-dependent attachment to human host cells. SARS-COV-2 uses the receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. Methods Metadichol was tested against TMPRSS2 ana ACE2 invitro using commercial available kits. Also it was tested against the live virus in Caco2 cells to test for inhibition of viral replication of SARS-COV-2.ResultsMetadichol®, a nano lipid formulation of long-chain alcohols, has been shown to inhibit TMPRSS2 (EC50 96 ng/ml). Compared to the inhibitor camostat mesylate (EC50 26000 ng/ml), it is 270 times more potent. Additionally, Metadichol® is also a weak inhibitor of ACE2 at 31 µg/ml. Further a live virus assay in Caco2 cells, Metadichol® inhibited SARS-CoV-2 replication with an EC90 of 0.16 µg/ml.Conclusions Metadichol inhibits SARS-COV-2 virus and since it a non toxic molecule can be easily tested in humans and as it has LD 50 of over 5000 mg/kilo and could help mitigate the crisis facing the world today.
... Metadichol® is a lipid formulation of long-chain alcohols, containing C26, C28 (more than 80%), and C30 [14]. Previous studies have demonstrated that Metadichol® inhibits viruses both in vitro and in vivo [15][16][17]. Thus, in this study, we evaluated the inhibitory effect of Metadichol, a nanoemulsion, against ACE2, angiotensin-converting enzyme (ACE), and TMPRSS2 and tested its efficacy in a SARS-CoV-2 antiviral assay. ...
... A previously published work [15] of antiviral data against other viruses is presented in Tables 3 and 4. The raw data depict the cytotoxicity of Metadichol in the absence of a virus in Vero cells measured using a neutral red assay. No viral CPE value was reported when the "cytotoxicity" was >75%. ...
Article
New pathogenic virus outbreaks, occurring with increasing regularity, are leading us to explore novel approaches, which will reduce the reliance on time-consuming vaccine modes to halt the outbreaks. The requirement is to find a universal approach to disarm any new and as yet unknown viruses as they appear. A promising approach could be targeting lipid membranes, which are common to all viruses and bacteria. The ongoing pandemic of severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2) has reaffirmed the importance of interactions between components of the host cell plasma membrane and the virus envelope as a critical mechanism of infection. Metadichol®, a nano lipid emulsion, has been examined and shown to be a strong candidate to help stop the proliferation of SARS-COV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce the infectivity of various types of viruses, including coronaviruses such as SARS-COV-2, by modifying lipid-dependent attachment to human host cells. SARS-COV-2 uses the receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. Metadichol®, a nano lipid formulation of long-chain alcohols, has been shown to inhibit TMPRSS2 (EC50 96 ng/ml). Compared to the inhibitor camostat mesylate (EC50 26000 ng/ml), it is 270 times more potent. Additionally, Metadichol® is also a weak inhibitor of ACE2 at 31 µg/ml. Further a live virus assay in Caco2 cells, Metadichol® inhibited SARS-CoV-2 replication with an EC90 of 0.16 µg/ml. Keywords: Coronavirus, SARS-COV-2, COVID-19, ACE2, TMPRSS2, VDR, Metadichol
... Metadichol ® is a nano lipid formulation of long-chain alcohols 14 . Metadichol has been shown to inhibit viruses in vitro and in vivo [15][16][17] . Metadichol was tested for its inhibitory actions against ACE2 and TMPRSS2 and in an antiviral assay with SARS-COV-2. ...
... Carvalho has recently demonstrated the potential of copaiba oilloaded NE against Zika Virus replication using in vitro Zika infection models in VERO E6 and HuH-7 cell lines (Carvalho, 2020). Although only one study regarding the antiviral efficiency of NE against arbovirus infections was found, many articles have recently described the potential of lipid formulations, including NE, to improve the antimicrobial activity of drugs, by modulating physiochemical properties (Ghildiyal and Gabrani, 2020) and the inherent antimicrobial properties presented by some fatty acids used to obtain pharmaceutical drug delivery nanosystems (Churchward et al., 2018;Donsì and Ferrari, 2016;Fletcher et al., 2020;Ma et al., 2016;Raghavan, 2016). ...
Article
Arboviruses are medically important viruses that cause high rates of infection all over the world. In addition, the severity of the symptoms and the inadequate diagnostic methods represent a challenge far beyond eradicating the vector. The lack of specific treatments for arbovirus infections reflects the imminent need for new research for safe and efficient medicines to treat these infections. Nanotechnology is an innovative approach currently used as a platform for developing new treatments, thus improving the biopharmaceutical properties of drugs. It can also be applied to the development of diagnostic devices, improving their detection capacity. The purpose of this paper is to review recent research on the use of nanotechnology for developing new treatments and detection devices for arbovirus infections. Interestingly, it was found that only a few studies report on the use of nanotechnology to treat arbovirus infections and that most of these reports focus on the fabrication of diagnostic tools. Also, some papers report on the use of nanotechnology for the development of vaccines, which in association with mosquito eradication programs could effectively reduce the high rates of infections by these viruses.
... Metadichol ® is a nano lipid formulation of long-chain alcohols 14 . Metadichol has been shown to inhibit viruses in vitro and in vivo [15][16][17] . Metadichol was tested for its inhibitory actions against ACE2 and TMPRSS2 and in an antiviral assay with SARS-COV-2. ...
Preprint
Full-text available
New pathogenic virus outbreaks, occurring with increasing regularity, are leading us to explore novel approaches, which will reduce the reliance on time-consuming vaccine modes to halt the outbreaks. The requirement is to find a universal approach to disarm any new and as yet unknown viruses as they appear. A promising approach could be targeting lipid membranes, which are common to all viruses and bacteria. The ongoing pandemic of severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2) has reaffirmed the importance of interactions between components of the host cell plasma membrane and the virus envelope as a critical mechanism of infection. Metadichol®, a nano lipid emulsion, has been examined and shown to be a strong candidate to help stop the proliferation of SARS-COV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce the infectivity of various types of viruses, including coronaviruses such as SARS-COV-2, by modifying lipid-dependent attachment to human host cells. SARS-COV-2 uses the receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. Metadichol®, a nano lipid formulation of long-chain alcohols, has been shown to inhibit TMPRSS2 (EC50 96 ng/ml). Compared to the inhibitor camostat mesylate (EC50 26000 ng/ml), it is 270 times more potent. Additionally, Metadichol® is also a extremely weak inhibitor of ACE2 at 31 µg/ml. Further a live virus assay in Caco2 cells, Metadichol® inhibited SARS-CoV-2 replication with an EC90 of 0.16 µg/ml.
... It is likely that Metadichol at higher concentrations behaves in a soap mimicking manner, by disrupting the lipid membrane, and at lower concentrations, it neutralizes the virus by a different mechanism. A previously published work (see ref 15) on antiviral assay this same "toxicity" was seen, and this is shown in Tables 5 and 6. ...
Preprint
Full-text available
New pathogenic virus outbreaks with increasing regularity are leading us to explore novel approaches, which will reduce the reliance on a time-consuming vaccine mode to halt the strike. The requirement is to find a universal approach to disarm any new and as yet unknown viruses as they appear. A promising approach could be by targeting the lipids membranes, common to all viruses and bacteria. The ongoing pandemic of the SARS-coronavirus 2 (SARS-CoV-2) has restated the importance of interactions between components of the host cell plasma membrane and the virus envelope as a critical mechanism of infection. Metadichol ®, a nano lipid emulsion, has been examined and shown to be a strong candidate to help stop the proliferation of the SARS-COV-2. Naturally derived substances, such long chain saturated lipid alcohols reduce the infectivity of various types of viruses, including the coronavirus like SARS-COV-2, by modifying the lipid-dependent attachment to human host cells. SARS-COV-2 uses the receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. Metadichol®, a nano lipid formulation of long-chain alcohols, has been shown to inhibit TMPRSS2 (EC50 of 96 ng/ml). Compared to the inhibitor Camostat Mesylate (26000 ng/ml), it is 270 times more potent. Also, Metadichol ® is a moderate inhibitor of ACE2 @ 31 µg/ml. In the SARS-COV2 antiviral assay using CACO2 cells, it has an EC90 of 0.16 µg/ml.
Article
Full-text available
Increasing outbreaks of new pathogenic viruses have promoted the exploration of novel alternatives to time-consuming vaccines. Thus, it is necessary to develop a universal approach to halt the spread of new and unknown viruses as they are discovered. One such promising approach is to target lipid membranes, which are common to all viruses and bacteria. The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reaffirmed the importance of interactions between the virus envelope and the host cell plasma membrane as a critical mechanism of infection. Metadichol®, a nanolipid emulsion of long-chain alcohols, has been demonstrated as a strong candidate that inhibits the proliferation of SARS-CoV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce viral infectivity, including that of coronaviruses (such as SARS-CoV-2) by modifying their lipid-dependent attachment mechanism to human host cells. The receptor ACE2 mediates the entry of SARS-CoV-2 into the host cells, whereas the serine protease TMPRSS2 primes the viral S protein. In this study, Metadichol® was found to be 270 times more potent an inhibitor of TMPRSS2 (EC50=96 ng/mL) than camostat mesylate (EC50=26000 ng/mL). Additionally, it inhibits ACE with an EC50 of 71 ng/mL, but it is a very weak inhibitor of ACE2 at an EC50 of 31 μg/mL. Furthermore, the live viral assay performed in Caco-2 cells revealed that Metadichol® inhibits SARS-CoV-2 replication at an EC90 of 0.16 μg/mL. Moreover, Metadichol® had an EC90 of 0.00037 μM, making it 2081 and 3371 times more potent than remdesivir (EC50=0.77 μM) and chloroquine (EC50=1.14 μM), respectively.
Preprint
Full-text available
New pathogenic virus outbreaks, occurring with increasing regularity, are leading us to explore novel approaches, which will reduce the reliance on time-consuming vaccine modes to halt the outbreaks. The requirement is to find a universal approach to disarm any new and as yet unknown viruses as they appear. A promising approach could be targeting lipid membranes, which are common to all viruses and bacteria. The ongoing pandemic of severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2) has reaffirmed the importance of interactions between components of the host cell plasma membrane and the virus envelope as a critical mechanism of infection. Metadichol®, a nano lipid emulsion, has been examined and shown to be a strong candidate to help stop the proliferation of SARS-COV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce the infectivity of various types of viruses, including coronaviruses such as SARS-COV-2, by modifying lipid-dependent attachment to human host cells. SARS-COV-2 uses the receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. Metadichol®, a nano lipid formulation of long-chain alcohols, has been shown to inhibit TMPRSS2 (EC50 96 ng/ml). Compared to the inhibitor camostat mesylate (EC50 26000 ng/ml), it is 270 times more potent. Additionally, Metadichol® is also a weak inhibitor of ACE2 at 31 µg/ml. Further a live virus assay in Caco2 cells, Metadichol® inhibited SARS-CoV-2 replication with an EC90 of 0.16 µg/ml.
Preprint
Full-text available
New pathogenic virus outbreaks, occurring with increasing regularity, are leading us to explore novel approaches, which will reduce the reliance on time-consuming vaccine modes to halt the outbreaks. The requirement is to find a universal approach to disarm any new and as yet unknown viruses as they appear. A promising approach could be targeting lipid membranes, which are common to all viruses and bacteria. The ongoing pandemic of severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2) has reaffirmed the importance of interactions between components of the host cell plasma membrane and the virus envelope as a critical mechanism of infection. Metadichol®, a nano lipid emulsion, has been examined and shown to be a strong candidate to help stop the proliferation of SARS-COV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce the infectivity of various types of viruses, including coronaviruses such as SARS-COV-2, by modifying lipid-dependent attachment to human host cells. SARS-COV-2 uses the receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. Metadichol®, a nano lipid formulation of long-chain alcohols, has been shown to inhibit TMPRSS2 (EC50 96 ng/ml). Compared to the inhibitor camostat mesylate (EC50 26000 ng/ml), it is 270 times more potent. Additionally, Metadichol® is also a weak inhibitor of ACE2 at 31 µg/ml. Further a live virus assay in Caco2 cells, Metadichol® inhibited SARS-CoV-2 replication with an EC90 of 0.16 µg/ml.
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Introduction: Inflammation is believed to be a contributing factor to many chronic diseases. The influence of vitamin D deficiency on inflammation is being explored but studies have not demonstrated a causative effect. Methods: Low serum 25(OH)D is also found in healthy persons exposed to adequate sunlight. Despite increased vitamin D supplementation inflammatory diseases are increasing. The current method of determining vitamin D status may be at fault. The level of 25(OH)D does not always reflect the level of 1,25(OH)2D. Assessment of both metabolites often reveals elevated 1,25(OH)2D, indicating abnormal vitamin D endocrine function. Findings: This article reviews vitamin D's influence on the immune system, examines the myths regarding vitamin D photosynthesis, discusses ways to accurately assess vitamin D status, describes the risks of supplementation, explains the effect of persistent infection on vitamin D metabolism and presents a novel immunotherapy which provides evidence of an infection connection to inflammation. Conclusion: Some authorities now believe that low 25(OH)D is a consequence of chronic inflammation rather than the cause. Research points to a bacterial etiology pathogenesis for an inflammatory disease process which results in high 1,25(OH)2D and low 25(OH)D. Immunotherapy, directed at eradicating persistent intracellular pathogens, corrects dysregulated vitamin D metabolism and resolves inflammatory symptoms.
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In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging.
Patent
The present invention provides methods of regulating physiological and metabolic parameters and of treating diseases by administering metadichol to a subject in need of such regulation and/or treatment. Metadichol can be administered as a liquid or gel formulation.
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Unlike its mosquito-borne relatives which can cause severe human diseases, including dengue, West Nile, and Japanese encephalitis viruses, Zika virus (ZIKV) has emerged from obscurity by its association with a suspected "congenital Zika syndrome", while causing asymptomatic or mild exanthematous febrile infections which are dengue- or rubella-like in infected individuals. Despite having been discovered in Uganda for almost 60 years, <20 human cases were reported before 2007. The massive epidemics in the Pacific islands associated with the ZIKV Asian lineage in 2007 and 2013 were followed by explosive outbreaks in Latin America in 2015. Although increased mosquito breeding associated with the El Niño effect superimposed on global warming is suspected, genetic changes in its RNA virus genome may have led to better adaptation to mosquitoes, other animal reservoirs, and human. We reviewed the epidemiology, clinical manifestation, virology, pathogenesis, laboratory diagnosis, management, and prevention of this emerging infection. Laboratory diagnosis can be confounded by cross-reactivity with other circulating flaviviruses. Besides mosquito bite and transplacental transmission, the risk of other potential routes of transmission by transfusion, transplantation, sexual activity, breastfeeding, respiratory droplet, and animal bite is discussed. Epidemic control requires adequate clearance of mosquito breeding grounds and personal protection against mosquito bite.
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The global burden of morbidity and mortality arising from viral infections is high; however, the development of effective therapeutics has been slow. As our understanding of innate immunity has expanded over recent years, knowledge of natural host defenses against viral infections has started to offer potential for novel therapeutic strategies. An area of current research interest is in understanding the roles played by naturally occurring cationic host defense peptides, such as the cathelicidins, in these innate antiviral host defenses across different species. This research also has the potential to inform the design of novel synthetic antiviral peptide analogs and/or provide rationale for therapies aimed at boosting the natural production of these peptides. In this review, we will discuss our knowledge of the antiviral activities of cathelicidins, an important family of cationic host defense peptides, and consider the implications for novel antiviral therapeutic approaches.
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Background: Respiratory syncytial virus (RSV) pneumonia after hematopoietic cell transplant (HCT) is associated with severe morbidity. Although RSV RNA has been detected in serum from patients with RSV lower respiratory disease (LRD) after HCT, the association with clinical outcomes has not been well established in multivariable models. Additionally, the role of antiviral treatment in HCT recipients has not been previously analyzed in multivariable models. Methods: We retrospectively identified HCT recipients with virologically confirmed RSV LRD and tested stored plasma/serum samples by quantitative reverse transcription polymerase chain reaction for RSV RNA. Risk factors for RSV RNA detection and the impact of RSV RNA in serum and antiviral therapy on outcomes were analyzed using multivariable Cox models. Results: RSV RNA was detected in plasma or serum from 28 of 92 (30%) patients at a median of 24.5 days following HCT and 2 days following LRD. In multivariable models, neutropenia, monocytopenia, thrombocytopenia, and mechanical ventilation increased the risk of plasma/serum RSV RNA detection; lymphopenia and steroid use did not. RSV RNA detection increased the risk of overall mortality in multivariable models (adjusted hazard ratio [aHR], 2.09 [P = .02]), whereas treatment with aerosolized ribavirin decreased the risk of overall mortality and pulmonary death (aHR, 0.33 [P = .001] and aHR 0.31 [P = .003], respectively). Conclusions: RSV RNA detection in plasma or serum may be a marker for lung injury and poor outcomes in HCT recipients with RSV LRD. Treatment with aerosolized ribavirin appeared to be protective against overall and pulmonary mortality.
The effects of policosanol (50–500 mg/kg) administered orally for 24 months to Sprague Dawley rats of both sexes were investigated. No differences related to daily clinical observations, weight gain, food consumption, or mortality (survival analysis) between groups were found. Histopathological study showed that the frequency of the occurrence of non-neoplastic and neoplastic (benign and malignant) lesions was similar in the control and policosanol-treated groups. The lesions observed in this study were similar to the spontaneous lesions reported in this species in previous studies. Since no drug-related increase in the occurrence of malignant or benign neoplasms was found, nor acceleration in tumors growth in any specific group was observed, this study shows no evidence of policosanol induced carcinogenicity in this strain of rats. © 1994 Wiley-Liss, Inc.
Article
Vitamin D has long been recognized as essential to the skeletal system. Newer evidence suggests that it also plays a major role regulating the immune system, perhaps including immune responses to viral infection. Interventional and observational epidemiological studies provide evidence that vitamin D deficiency may confer increased risk of influenza and respiratory tract infection. Vitamin D deficiency is also prevalent among patients with HIV infection. Cell culture experiments support the thesis that vitamin D has direct anti-viral effects particularly against enveloped viruses. Though vitamin D's anti-viral mechanism has not been fully established, it may be linked to vitamin D's ability to up-regulate the anti-microbial peptides LL-37 and human beta defensin 2. Additional studies are necessary to fully elucidate the efficacy and mechanism of vitamin D as an anti-viral agent.