Exploring the Synergistic Potential of LL37 and Niacinamide as an Antiviral Strategy Against SARS-CoV-2


The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted extensive research into understanding its mechanisms of infection and developing effective countermeasures.

Central to SARS-CoV-2’s infectivity is the engagement of its spike protein with the angiotensin converting enzyme 2 (ACE2) receptor on host cell membranes.

Numerous vaccine strategies have targeted the spike protein to disrupt this interaction and prevent viral infection. However, the intricate relationship between ACE2 expression and viral tropism, especially in tissues like the skin, adds complexity to the understanding of the virus-host interaction.

Skin as a Unique Case Study

The skin, an organ expressing ACE2 in the epidermis and keratinocytes, presents an intriguing case. Despite the competence of epidermal keratinocytes for SARS-CoV-2 infection, the skin is not considered a primary route of infection. This apparent paradox suggests the existence of endogenous defense mechanisms within the skin that inhibit viral infection.

One such mechanism is the constitutive secretion of antimicrobial peptides (AMPs), with human cathelicidin (LL37) being a notable player.

LL37 as a Multifaceted Antimicrobial Agent

Previous reports highlight LL37 as a potent inhibitor of SARS-CoV-2, exerting its effects through interactions with both ACE2 and Spike proteins. Beyond its antiviral properties, LL37 has demonstrated efficacy against various viruses, including influenza A virus (IAV), human immunodeficiency virus (HIV), Zika virus (ZIKV), and dengue virus (DENV-2). Moreover, LL37 modulates the host immune system, generating a comprehensive response against infections.

Challenges in Therapeutic Application

Despite the promising antimicrobial properties of LL37, its therapeutic application faces limitations due to the peptide’s cationic nature, leading to self-aggregation and subsequent issues with bioavailability and efficacy. Overcoming this challenge is crucial for harnessing the full potential of LL37 as an antiviral agent.

Niacinamide as a Solution

To address the limitations of LL37, we turn to niacinamide (vitamin B3), a hydrotrope widely utilized in cosmeceutical and pharmaceutical products. Niacinamide not only enhances the solubility and bioavailability of biomolecules but has also been shown to induce the secretion of antimicrobial peptides from skin cells. Furthermore, niacinamide enhances the activity of LL37, particularly against bacterial cell membranes.

Hypothesis and Objectives

In light of the above, we hypothesize that the addition of niacinamide could synergistically enhance the efficacy of LL37 as an antiviral agent. This study aims to explore the mechanistic insights into this potential synergy and assess the practical applications of the LL37-niacinamide combination against a respiratory virus, with a particular focus on SARS-CoV-2.


The research will involve in vitro experiments using human epidermal keratinocytes exposed to SARS-CoV-2 to evaluate the inhibitory effects of LL37, niacinamide, and their combination. Various assays, including viral infectivity assessments, AMP secretion profiling, and immune response modulation studies, will be conducted to elucidate the underlying mechanisms.


The intricacies of SARS-CoV-2 variants, particularly those showcasing heightened transmissibility and increased disease severity, have been closely examined in the preceding sections. Notably, mutations in the receptor binding domain (RBD) of the spike protein have been linked to these characteristics, posing a substantial challenge to existing vaccines relying on spike protein antigens. The risk of vaccine escape looms large in the face of evolving viral strains.

A pivotal aspect of viral evasion elucidated in this exploration is the heavy glycan coating of spike proteins. This coating operates as a protective shield, rendering spike proteins less detectable to the immune system. The implications of this immune evasion strategy extend to vaccine effectiveness, necessitating a shift in focus toward alternative strategies.

The core argument of this discourse revolves around the potential efficacy of LL37 in neutralizing SARS-CoV-2 by targeting its envelope. This strategic shift, from spike protein-centric approaches to a focus on the conserved viral envelope originating from the host cell, presents a promising avenue. The data presented substantiates the hypothesis that LL37, particularly when coupled with niacinamide, holds significant potential as an alternative therapeutic approach against viral infections.

The discussion extends to the synergistic effect observed when niacinamide is introduced, enhancing the antiviral activity of LL37. The inclusion of insights gleaned from symptomatic patient samples reinforces the proposition that strategies augmenting the efficacy of antimicrobial peptides could be instrumental in fortifying the immune response against viral infections.

The therapeutic implications are profound, with the discussion proposing the consideration of exogenous administration of the AMP alongside niacinamide. This approach, or other methods designed to boost endogenous peptide production, emerges as a potential method not only to impede viral transmission but also to serve as an effective post-infection therapy, mitigating viral load and disease severity.

Looking forward, the discourse directs attention to the necessity of developing a delivery system for the LL37 and niacinamide formulation directly within the respiratory tract. Drawing inspiration from current vaccine delivery methods, such as nebulizers or nasal sprays, this avenue presents a tangible next step in translating these findings into practical therapeutic modalities. Animal models of SARS-CoV-2 infection are identified as invaluable tools for refining and validating this proposed therapeutic approach.

In summary, this discussion lays the groundwork for continued exploration and development of LL37 and niacinamide as a promising strategy against SARS-CoV-2 infections. It emphasizes the imperative for innovative, targeted therapeutic approaches as we navigate the dynamic landscape of viral evolution and infectious diseases.


As the world continues to grapple with the challenges posed by SARS-CoV-2, exploring innovative antiviral strategies becomes imperative. The proposed research, centered around the synergistic potential of LL37 and niacinamide, holds promise not only for addressing the limitations of LL37 but also for advancing our understanding of skin-based antiviral defenses. If successful, this study could pave the way for the development of novel therapeutic approaches in the ongoing battle against respiratory viruses, including SARS-CoV-2.

reference link : https://www.frontiersin.org/articles/10.3389/fimmu.2023.1255478/full


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