COVID-19 News: Karnataka-India Study Shows That Niacinamide Enhances Cathelicidin Mediated SARS-CoV-2 Membrane Disruption
: As the world battles the ongoing threat of COVID-19, a recent study conducted in Karnataka, India, sheds light on a promising strategy to enhance the body's defense against SARS-CoV-2. The study covered in this COVID-19 News
report, was a collaborative effort between the Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, Manipal Academy of Higher Education (MAHE), National Centre for Biological Sciences (TIFR), and Unilever R&D in both Bangalore, Karnataka, and Trumbull, United States, focuses on the potential of niacinamide in amplifying the antiviral activity of the human cathelicidin peptide (LL37).
Effect of niacinamide on LL37 (A) Viral gene expression at different concentrations of LL37 in the presence of niacinamide (qRT-PCR) (n=3) (B) Effect of niacinamide combined with LL37 on the TCID50/ml of various SARS-CoV-2 strains (n=3) (C) Partial sequence of the amphipathic LL37 peptide is represented with an idealized helical wheel (left) with residues colored according to their nature (hydrophobic, grey; polar, green; acidic, red; basic, blue). Right, two views of the LL37 peptide (color scheme same as the wheel; sidechains, black) overlaid with niacinamide molecules (grey) within 6 Å of the peptide (over 10 ns). The 10 ns overlay emphasizes the solvent-like encapsulation of the peptide by niacinamide with greater residence over the hydrophobic face of the helix than the polar/charged face (D) Contribution of each residue of LL37 towards interaction with niacinamide from MD simulations (mean of 3 independent simulations, errors propagated from each replicate). Residues contributing >1 kJ mol-1 are labelled (E) Niacinamide in the membrane forms hydrogen bonds with the Lys (K) and Arg (R) residues of LL37. Whereas, the aliphatic residues of LL37 which preferentially interacted with niacinamide in solution (D) are now predominantly engaged with the hydrophobic acyl chains and so, are unable to contribute much to bind niacinamide (F) Representative snapshot (left) of niacinamide penetrating deeper than water into the hydrophobic core of the membrane (LL37, black peptide; lipid acyl chains, grey lines; niacinamide, space filling; water, orange) which is quantified on the right, averaging the molecular density (membrane, black; niacinamide, green; water, orange) over the entire 200 ns trajectory (5 replicates, mean ± SD) [Statistical analysis was done using student t-test for (A) and two-way ANOVA for (B), *p≤0.05, **p≤0.001, ***p≤0.0001].
The Challenge of SARS-CoV-2 Variants
The persistent evolution of SARS-CoV-2 variants poses a significant challenge to global vaccination efforts, necessitating the exploration of complementary strategies for a sustainable containment plan. The study emphasizes the importance of mobilizing the body's antimicrobial peptides (AMPs), specifically LL37, to combat SARS-CoV-2 infection. LL37, found in epithelial barriers and bodily fluids, has demonstrated the ability to neutralize multiple strains of the virus.
LL37 as an Antiviral Agent
Previous research indicates that LL37 inhibits SARS-CoV-2 by i
nteracting with the viral spike protein and ACE2 receptor. It has also exhibited antiviral properties against various viruses, including influenza A, HIV, Zika, and dengue. However, the therapeutic application of LL37 faces challenges due to its tendency to self-aggregate, limiting its bioavailability and efficacy.
Niacinamide's Role in Enhancing LL37
To address the limitations of LL37, the study explores the use of niacinamide (vitamin B3) as a hydrotrope. Niacinamide has been widely utilized in cosmeceutical and pharmaceutical products, demonstrating antimicrobial properties and enhancing LL37 activity against bacterial cell membranes. The hypothesis is that niacinamide can increase the solubility and bioavailability of LL37, thereby improving its effectiveness.
The research team conducted experiments to assess the effectiveness of LL37 against SARS-CoV-2. The results demonstrated a dose-dependent decrease in viral gene expression upon LL37 treatment, with consistent efficacy against different variants of the virus. Molecular dynamics simulations and membrane disruption assays indicated that LL37 interacts with viral membranes, disrupting their integrity.
Niacinamide's Dual Effect
The study reveals that niacinamide enhances the antiviral activity of LL37 through a dual effect. Firstly, it increases the aqueous solubility of LL37, improving its bioavailability. Secondly, niacinamide cooperates with LL37 to destabilize viral membranes, offering a comprehensive strategy against SARS-CoV-2.
An intriguing finding of the study is the inverse correlation between LL37 levels and the severity of COVID-19 in patients. Saliva analysis showed that symptomatic individuals had significantly lower LL37 levels than uninfected individuals, suggesting that enhancing LL37 activity could be a therapeutic avenue to mitigate disease severity.
Implications and Future Directions
The research underscores the potential of combining niacinamide with LL37 as a potent antiviral formulation targeting various SARS-CoV-2 variants. The study proposes further exploration of this combination as a therapeutic strategy to overcome vaccine escape and limit viral transmission.
Moreover, the research suggests that exogenous supplementation of niacinamide in symptomatic COVID-19 patients may enhance the activity of naturally produced AMPs, providing an additional layer of protection. The next steps involve developing a delivery system for the LL37 and niacinamide formulation, possibly through nebulizers or nasal sprays, for effective respiratory tract administration.
In the ongoing battle against SARS-CoV-2, the Karnataka-India study offers a ray of hope by unveiling the synergistic potential of niacinamide and LL37 in combating the virus. The findings not only highlight the significance of harnessing the body's innate defense mechanisms but also open avenues for innovative therapeutic interventions to control the evolving landscape of COVID-19. As research progresses, the combination of niacinamide and LL37 could emerge as a crucial strategy in the global effort to curb the impact of SARS-CoV-2 variants.
The study findings were published in the peer reviewed journal: Frontiers in Immunology.
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