An arylamide foldamer, and unlike most peptidic-based small molecules (e.g., Pexiganan), Brilacidin is not subject to the traditional shortcomings of antimicrobial peptide (AMP)-based compounds, including rapid proteolytic degradation. Instead, by using sophisticated coarse-grain computer modeling that mimicked the behavior of natural defensins (electrostatics, lipophicility, etc.), it was designed (pdfs) to be smaller (one-tenth the size) and then fine-tuned to exhibit enhanced pharmacological properties—more easily and much less expensively synthesized, more stable (a rigid backbone), more potent (by a 100-fold) and more selective (by a 1000-fold).
Beyond its antimicrobial properties—which itself can play a major role in treating certain inflammatory diseases given the association between pathogens and host organisms, inflammation and infection (e.g., see the link between Enterobacteriaceae and IBD; the link between Crohn’s and E. coli [against which HDP-Mimetics have shown activity]; and the link between Crohn’s and infections, including fungal ones—Brilacidin functions through the cyclic AMP/cyclic GMP pathways to suppress pro-inflammatory cytokines and chemokines, such as TNF-α, IL-1β, IL-6, IL-8, MIP2-α, MCP-1 and MMP-9.
Brilacidin’s inhibition of PDE4—a predominant phosphodiesterase expressed in neutrophils, T cells, macrophages and keratinocytes—leads to an increase in the intracellular cAMP concentration, thereby reducing the production of pro-inflammatory mediators and increasing anti-inflammatory mediators.
Additional research is underway to determine Brilacidin's potential effect on IL-17, a central driver of most inflammatory diseases, including many skin diseases.
Linked to below is a Nature Reviews Drug Discovery series on the IL-17 pathway.