BREAKING! Bangalore Study Finds That Vitamin B3 Can Be Used to Enhance A Natural Antiviral In Humans Called Cathelicidin To Inhibit SARS-CoV-2!

COVID-19 Supplements: Indian researchers from the city of Bangalore (Bengaluru) in Karnataka-India have found in a new study that niacinamide or Vitamin B3 (niacin) can be used to enhance a natural occurring antiviral in humans called cathelicidin (LL37) to destroy the membrane of the SARS-CoV-2 virus, thus inhibiting its replication.


 
The study team comprised of medical scientist from the Institute for Stem Cell Science and Regenerative Medicine (inStem)-Bangalore, Manipal Academy of Higher Education (MAHE)-Manipal, National Centre for Biological Sciences (TIFR)-Bangalore, Unilever R&D-Bangalore and Unilever R&D Trumbull, Connecticut-USA.
 
The rapid and constant emergence of various SARS-CoV-2 variants and subvariants is threatening to compromise the effectiveness of worldwide vaccination programs and even current antivirals being used, highlighting the need for complementary strategies for a sustainable containment plan.
 
Corresponding author, Dr Colin Jamora from the Institute for Stem Cell Science and Regenerative Medicine in Bangalore told Thailand Medical News, “A more better strategy is to mobilize the body′s own antimicrobial peptides (AMPs), to combat SARS-CoV-2 infection and propagation.”
 
The study team found that human cathelicidin (LL37), an AMP found at epithelial barriers as well as in various bodily fluids, has the capacity to neutralize multiple strains of SARS-CoV-2 including the various current new Omicron variants.
 
Importantly biophysical and computational studies indicate that LL37′s mechanism of action is through the disruption of the viral membrane. This antiviral activity of LL37 is enhanced by the hydrotropic action of niacinamide or Vitamin B3, which may increase the bioavailability of the AMP.
 
The study findings importantly showed an inverse correlation between LL37 levels and disease severity of COVID-19 positive patients, suggesting enhancement of AMP response as an interesting therapeutic avenue to mitigate disease severity.
 
The study team said that the combination of niacinamide and LL37 is a potent antiviral formulation that targets viral membranes of various variants and can potentially overcome vaccine escape.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.08.26.505399v1
 
It should be noted that already, many past studies had shown that Vitamin in either the form of niacin or niacinamide can also help boost the immune system to fight against various viruses.
https://pubmed.ncbi.nlm.nih.gov/33403940/
 
https://academic.oup.com/cid/article/36/4/453/439703
 
Another recent study had indicated that low levels of Vitamin B3 could be the reason behind COVID-19 severity.
https://www.mdpi.com/1422-0067/23/8/4309/htm a>
 
Studies have also indicated that Vitamin B3 could mitigate some of the inflammatory process triggered in SARS-CoV-2 infection. https://www.nature.com/articles/s41420-020-00297-9
 
https://osf.io/uec3r/
 
https://www.degruyter.com/document/doi/10.1515/jbcpp-2021-0111/html
 
https://actascientific.com/ASPS/pdf/ASPS-04-0526.pdf
 
https://link.springer.com/article/10.1007/s10787-021-00826-7
 
The human AMP cathelicidin (LL37) has been shown to target various classes of viruses including respiratory viruses.
https://pubmed.ncbi.nlm.nih.gov/23052388/
 
https://pubmed.ncbi.nlm.nih.gov/24023689/
 
https://pubmed.ncbi.nlm.nih.gov/17627504/
 
In order to ascertain whether LL37 is effective against SARS-CoV-2, the study team incubated the virus with this AMP and assessed its ability to infect an intestinal epithelial cell (Caco2) as a reporter.
 
The study findings showed a dose-dependent decrease in viral gene expression upon treatment with LL37.
 
Importantly, this LL37 mediated effect was also observed in other SARS-CoV-2 variants (alpha, kappa, delta, and omicron).
 
The study findings were confirmed by tissue-culture infectious dose (TCID50) assays.
 
It should be noted that already a past study had suggested that LL37 can interact with the spike protein and the ACE2 receptor and possibly occlude the interaction surface between them.
https://pubmed.ncbi.nlm.nih.gov/33849267/
 
As LL37 has been known to interact with, and aggregate on membranes, the study team hypothesized that LL37 may inhibit viral infection in a Spike/Ace2 independent manner.
https://pubmed.ncbi.nlm.nih.gov/10417311/
 
The COVID-19 Supplements study team hence compared the neutralizing capacity of LL37 against viruses of different tropism, namely VSV-G and S1 pseudo-typed lentivirus particles.
 
The study team found a comparable reduction in transduction when both pseudo-typed lentivirus particles were treated with increasing amounts of LL37.
 
The findings are consistent with reports that LL37, a cationic peptide, can execute its antimicrobial activity by attacking the negatively charged membrane of viruses.
https://www.sciencedirect.com/science/article/pii/S0005273615003685
 
It is already known that enveloped viruses such as the SARS-CoV-2 coronavirus that assemble virions by budding off from the endoplasmic reticulum membrane have a negatively charged membrane due to a higher content of phosphatidylserine (PS).
https://pubmed.ncbi.nlm.nih.gov/26915293/
 
https://pubmed.ncbi.nlm.nih.gov/8566406/
 
The study team prepared three different vesicles in which PS composition was varied according to the published range of ER-derived virions to mimic the membrane composition of a generic coronavirus.
 
The study findings showed that increasing the percentage of PS resulted in an increase in the negative surface charge on the vesicles, which was neutralized by the presence of LL37.
 
The findings suggest that the positively charged peptide can coat the outer leaflet of the bilayer by electrostatic interactions.
 
In order to determine the consequence of the interaction of LL37 with the vesicles, the study team assayed whether membrane integrity was compromised.
 
Utilizing a fluorescence resonance energy transfer (FRET) based membrane disruption assay, the study team observed reduction in FRET (fluorescence recovery at 530nm) when vesicles were treated with LL37.
 
These findings indicate that LL37 is more effective in interacting with and disrupting membranes with a higher negative charge.
 
It should also be note that disease severity of several viral respiratory infections has been inversely correlated with LL37 levels.
https://pubmed.ncbi.nlm.nih.gov/28541502/
 
As it has already been shown that salivary burden of SARS-CoV-2 correlates with disease severity in patients, the study team compared the levels of secreted LL37 in the saliva of SARS-CoV-2 infected and uninfected individuals
 
It was found that symptomatic individuals had on average ~3-fold less LL37 than uninfected individuals.
 
Significantly, asymptomatic positive patients had equivalent levels of LL37 as uninfected individuals. These results suggest that lower LL37 levels may potentially render individuals more susceptible to a symptomatic infection.
 
As a result of lower levels of LL37 being associated with the symptomatic COVID-19 patient group, the study team speculated that increasing the level of LL37 or enhancing the activity of the existing LL37 might serve as a potential means of combating SARSCoV-2 infection.
 
One method of enhancing the activity of LL37 is to decrease its inherent self-aggregation and thereby increase its bioavailability. https://pubmed.ncbi.nlm.nih.gov/10417311/
 
Interestingly, a common approach to prevent aggregation is through the use of a hydrotrope such as niacinamide (vitamin B3). It is a generally regarded as safe (GRAS) substance used to increase the solubility, and therefore the activity, of various drugs. https://pubs.rsc.org/en/content/articlelanding/2015/cp/c4cp05414h/unauth
 
Importantly, the study team did observe that LL37 supplemented with niacinamide exhibited an enhanced potency against infection by different variants of SARS-CoV-2.
 
In order to comprehend the mechanism of LL37 interaction with lipid membranes in the presence of niacinamide, the study team used atomistic molecular dynamics (MD) simulations.
 
The simulations support the hydrotropic solubilization of LL37 by an aqueous solution of niacinamide. The simulations suggest that encapsulating of aggregation prone residues of LL37 by niacinamide would likely improve the bioavailability of the peptide.
 
The study team also employed molecular dynamics simulation to investigate the early steps of LL37 adsorption on viral envelope-like membranes in the presence of niacinamide.
 
The simulations demonstrated the lipid acyl chains and headgroups interacting with the LL37 peptide. These interactions pull the peptide into the membrane resulting in local thinning in the bilayer and ultimately a dramatic destabilization of membrane, with a concomitant destabilization of lipid ordering. This configuration meant that the charged amino acid residues of LL37 faced the solvent and were free to interact with niacinamide.
 
The simulation predicts that niacinamide also penetrates into the membrane and may synergize with LL37 to disrupt the membrane.
 
The study team concluded that niacinamide has dual activities:
 
-1) hydrotropically increase the aqueous solubility of LL37, thereby rendering it more bioavailable.
 
-2) cooperate with the peptide to destabilize membrane.
 
The study validated the findings of these computational results by performing a FRET-based membrane disruption assay using artificial viral membranes  in the presence of LL37 and niacinamide.
 
Consistent with simulation predictions, the study team observed that membrane disruption of liposomes by LL37 was enhanced in combination with niacinamide, while niacinamide by itself was not antiviral.
 
To further test whether the effect of niacinamide can be reproduced with naturally produced AMPs, the study team analyzed its effect on AMPs that are highly secreted in saliva and from the skin.
 
The study team found that human saliva exhibits antiviral activity against SARS-CoV-2, which can be potentiated upon supplementation with niacinamide.
 
The researchers also observed that skin scrubs supplemented with niacinamide exhibited antiviral activity.
 
The human body naturally synthesizes niacinamide, but interestingly, the biosynthetic pathways and precursor leading to niacinamide production are downregulated in symptomatic COVID-19 patients.
https://pubmed.ncbi.nlm.nih.gov/32492406/
 
Hence, exogenous supplementation of niacinamide in symptomatic patients may potentiate the activity of naturally produced AMPs from the body’s epithelia.
 
The study findings show that the AMP LL37 has the potential to neutralize the SARS-CoV-2 viral infection by targeting its envelope and niacinamide further enhances this antiviral activity of the peptide.
 
The data on the symptomatic patient samples further substantiate this hypothesis and argues for an approach that would entail enhancing the efficacy of antimicrobial peptides for protection against viral infections. Therefore, either exogenous administration of the AMP with niacinamide or other strategies to boost the endogenous production of the peptide in combination with niacinamide could be a potent method to not only block viral transmission, but may be an effective therapy to limit viral load and disease severity of a patient post infection.
 
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