Peptidomimetic Drugs: In Vitro, In Vivo & mechanistic Studies of 5-12mer Antimicrobial & Antiviral Peptoids to Treat Respiratory Infections
- Type: Conference Presentation
- Conference Type: AIChE Annual Meeting
- Presentation Date: November 16, 2020
- Duration: 22 minutes
- Skill Level: Intermediate
- PDHs: 0.40
Growing pathogen resistance to conventional antibiotics that cause respiratory infections has spurred the exploration of bioengineered antimicrobial peptides (AMPs) and analogues as novel anti-infective agents. AMPs are cationic, amphipathic compounds that can both self-assemble in aqueous solution, and interact with both pathogen and host cell membranes in complex ways. Since the bioavailability of natural peptides is limited by proteolysis, non-natural AMP mimics are interesting as more robust and biostable antimicrobials, and offer distinct advantages as potential clinical therapeutics. We report here on our experimental exploration of the development of poly-N-substituted glycines (peptoids) as a new class of biomimetic antimicrobial drugs, via multiple approaches including several different in vitro assays and in vivo mouse studies. After studying more than 120 peptoid sequence variants, we identified a number of unique peptoids that exhibit potent, broad-spectrum antibacterial in vitro activity, and which have a unique, biomimetic mechanism of action, similar to that of the human antibacterial peptide LL-37: bacterial rigidification. In our most recent in vivo testing, mice were infected intratracheally with bioluminescent Pseudomonas aeruginosa, then treated by our TM5 peptoid, providing a significant reduction in bacterial loads compared to untreated animals. TM5 peptoid was also well tolerated in the lung by mice. In addition, new super-resolution fluorescence videomicroscopy studies confirm that these peptoids rapidly ârigidifyâ bacterial cytoplasm, just like natural cathelicidin AMPs (LL-37, cecropin). Our latest experimental results show that like LL-37, as well, our peptoids have antiviral activity as well. Finally, we have shown via SAXS studies that the activity and potency of these cationic, amphipathic TM5 peptoids is dictated entirely by their self-assembly into stable, ellipsoidal micelles. Taken together, these results show the highly promising potential clinical applicability of these 5-12mer peptoids.
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