Innovation Pharmaceuticals wanted to bring attention to recently published Host Defense Peptide/Protein (HDP) research (linked to below) that supports the development of HDP-based therapeutics, including synthetic or mimetic versions, such as Brilacidin.
Brilacidin’s Development as an HDP-Mimetic in Context
An arylamide foldamer and unlike peptidic-based small molecules, Brilacidin is not subject to traditional shortcomings of peptide-based compounds (e.g., rapid proteolytic degradation, toxicity and tissue distribution concerns, cost of manufacturing, etc.), which have limited development prospects. Instead, by using sophisticated coarse grain computer modeling that mimicked the actions of natural defensins (electrostatics, lipophicility), Brilacidin was designed (pdf) de novo—originally by University of Pennsylvania-based researchers, including two National Academy of Science members: William DeGrado and Michael Klein—to be smaller (one-tenth the size) and then further fine-tuned to exhibit enhanced pharmacological properties. This made the drug candidate more easily and much less expensively synthesized; more stable (a rigid backbone and sidechains); more potent; and more selective. Biocomputational aspects of Brilacidin’s development have resulted in the drug candidate exhibiting more tailored exposure and efficacy.
Favorable patient outcomes have now been anchored across three different clinical indications (Ulcerative Proctitis/Ulcerative Proctosigmoiditis, Oral Mucositis, and Acute Bacterial Skin and Skin Structure Infection) in successful clinical trials, with Brilacidin administered locally or systemically. Of note, the academic literature suggests a defensin/mucin deficiency in Inflammatory Bowel Disease, impacting the mucosal immune system, indicating Brilacidin may have a compensatory effect in this regard.
Recent Academic Literature on HDPs (2020 - 2016) [updated]
· Divyashree M, et al (2020). Clinical Applications of Antimicrobial Peptides (AMPs): Where Do We Stand Now? (pdf) Protein Pept Lett 2020;27(3):120-134.
· Umnyakova ES, et al (2020). Human Antimicrobial Peptides in Autoimmunity. (pdf) Autoimmunity. 2020 Jan 8:1-11.
· Prasad SV, et al (2020). Expression and Function of Host Defense Peptides at Inflammation Sites. (pdf) Int. J. Mol. Sci. 2020, 21(1), 104.
· Bhopale GM (2019). Antimicrobial Peptides: A Promising Avenue for Human Healthcare. Curr Pharm Biotechnol. 2019 Oct 11.
· Haney EF, Straus SK, and Hancock REW (2019). Reassessing the Host Defense Peptide Landscape. (pdf) Front Chem. Feb 4;7:43 eCollection 2019.
· Nicolas, I, et al (2019). Novel Antibiotics Effective Against Gram-Positive and -Negative Multi-Resistant Bacteria with Limited Resistance. (pdf) PLoS Biol 17(7): e3000337.
· Kamarauzzaman NF, et al (2019). Antimicrobial Polymers: The Potential Replacement of Existing Antibiotics? (pdf) Int. J. Mol. Sci. 2019, 20(11), 2747.
· Amerikova, A, et al (2019). Antimicrobial Activity, Mechanism of Action, and Methods for Stabilisation of Defensins as New Therapeutic Agents. (pdf) Biotechnology & Biotechnological Equipment 33(1):671-682 · January 2019.
· Kuppusamy R, et al (2019). Short Cationic Peptidomimetic Antimicrobials. (pdf) Antibiotics 2019, 8(2), 44.
· Palermo EF, et al (2019). Viewpoint: Antibacterial Activity of Polymers: Discussions on the Nature of Amphiphilic Balance. In: Angewandte Chemie (International Edition).
· Sun E, et al (2018). Host Defense (Antimicrobial) Peptides (Chapter 10). (pdf) In: Peptide Applications in Biomedicine, Biotechnology and Bioengineering. 2018: 253-286.
· Avci FG, Akbulut BS and Ozkirimli E (2018). Membrane Active Peptides and Their Biophysical Characterization. (pdf) Biomolecules. 2018 Aug 22;8(3). pii: E77.
· Boto A, Perez de la Lastra JM, Gonzalez CC (2018). The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs. (pdf) Molecules. 2018 23(2) pii: E311.
· Naafs M AB (2018). The Antimicrobial Peptides: Ready for Clinical Trials? (pdf) Biomed J Sci & Tech Res. 2018: Vol 7, Issue 4.
· Li J, et al (2017). Membrane Active Antimicrobial Peptides: Translating Mechanistic Insights to Design. (pdf) Front Neurosci. Feb 14;11:73. eCollection 2017.
· Chieosilapatham P, Ogawa H, and Niyonsaba F (2017). Current Insights into the Role of Human B-Defensins in Atopic Dermatitis. (pdf) Clin Exp Immunol. 2017 Nov;190(2):155-166. Epub 2017 Aug 4.
· Coretti L, et al (2017). The Interplay Between Defensins and Microbiota in Crohn’s Disease. (pdf) Mediators of Inflammation. Volume 2017, Article ID 8392523, 8 pages.
· Scott RW, Tew GN (2017). Mimics of Host Defense Proteins; Strategies for Translation to Therapeutic Applications. (pdf) Curr Top Med Chem. 2017;17(5):576-589.
· Gurwitz D (2017). Peptide Mimetics: Fast-Forward Look. (pdf) Drug Dev Res. 2017 Sep;78(6):231-235. Epub 2017 Aug 17.
· Niyonsaba F (2016). Novel Insight into the Role of Antimicrobial (Host Defense) Peptides/Proteins in Human Skin Diseases. (pdf) 2016 Juntendo Medical Journal. Volume 62 Issue 2 Pages 120-131.
“The multi-faceted nature of HDPs and their ability to influence a wide range of biological processes opens the door to expanding our understanding of other activity landscapes within the chemical space of HDPs. As our understanding of these other activity types improves, and the mechanistic details underpinning these other processes are laid bare, this will undoubtedly lead to the development of HDP based drugs that are effective against infectious diseases as well as inflammatory conditions.”
Source: Haney EF, Straus SK, and Hancock REW (2019). “Reassessing the Host Defense Peptide Landscape.” Review Article Front. Chem., 04 February 2019; also see Sun E, et al (2018). “Host Defense (Antimicrobial) Peptides” (Chapter 10) (pdf) In: Peptide Applications in Biomedicine, Biotechnology and Bioengineering, 253-285, 2018.