The commentary and corresponding articles summarize the potential of (non)peptide-mimetics/defensin-mimetics ("peptoids"), particularly as novel oral therapeutics, considering the central role defensins play in innate immunity and the host defense response.
· “Presently, only a few peptides are used as therapeutics in their natural form, most notably insulin and erythropoietin, while others are in clinical trials, for example, nasal oxytocin as treatment for autism spectrum disorders [Parker et al., 2017]. However, similarly to all peptides, peptide hormones are not suitable for oral administration, being rapidly degraded by the gastrointestinal system, which necessitates their administration by intramuscular injection, or as nasal sprays, for therapeutic use, limiting their utility as therapeutics [Varamini and Toth, 2016]. Peptide mimetics, non-peptide compounds that mimic or modulate the action of natural peptides, have the potential to circumvent this barrier and be suitable for oral administration.”
· “Given the central role of peptides in endocrinology and intercellular interactions, including between host and pathogens, an untapped potential exists for the development of novel peptide mimetic drugs.”
· “The author's personal view is that, as a fast-forward optimistic projection, peptide mimetics could become among the best therapeutics for future generations.”
Brilacidin is Innovation’s lead defensin-mimetic drug candidate that has been evaluated in Phase 2 trials in: Acute Bacterial Skin and Skin Structure Infections (ABSSSI); Ulcerative Proctitis/Proctosigmoiditis (UP/S), a type of Inflammatory Bowel Disease (IBD); and Oral Mucositis, a common and severe side-effect of chemoradiation associated with head and neck cancer. By leveraging data obtained from these clinical trials, and by advancing oral and topical formulations, future Brilacidin trials are planned in Crohn’s Disease, as well as dermatological conditions — Atopic Dermatitis, Hidradenitis Suppurativa and Acne.
Brilacidin, as an arylamide foldamer and unlike peptidic-based small molecules (e.g., Pexiganan), is not subject to the traditional shortcomings of peptide-based compounds, including rapid proteolytic degradation that makes them ill-suited for oral delivery. Instead, by using sophisticated coarse-grain computer modeling that mimicked the actions of natural defensins (e.g., electrostatics, lipophicility), Brilacidin was designed 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).
This biocomputational aspect of Brilacidin’s development has resulted in a drug candidate better tailored for its intended uses.