세미나 서지원 교수 [GIST, 화학과] - Engineering natural peptides for the discovery of novel anti-infectives
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일시: 2024년 12월 5일 (목) 오후 5시
장소: 과학관 B130호
초록: Interest in peptides has grown significantly in pharmaceutical research and development. Currently, more than 60 US FDA approved peptide-based drugs are on the market, and over 170 peptide therapeutics are undergoing clinical evaluation. The therapeutic potential of peptides is largely influenced by their physicochemical properties and proteolytic stability profiles. To enhance these profiles, various strategies have been developed, including chemical modifications such as macrocyclization, N-methylation, and substitution with N-substituted glycines (peptoids). These engineered peptides are capable of recognizing large surface areas on targets, including protein-protein interactions (PPIs) and phospholipid membranes, thus expanding their applicability within the "beyond rule of five" (bRo5) chemical space.
Overuse of conventional antibiotics and the slow pace of new antibiotic drug development contribute to antimicrobial resistance (AMR). Multidrug-resistant (MDR) infections pose a serious public health threat, highlighting the urgent need for novel antibiotics. Antimicrobial peptides (AMPs) have emerged as a promising platform to fight against MDR bacteria ensuring broad-spectrum antimicrobial activity and relatively low resistance emergence, with over 27 AMPs in clinical development. 1 However, most peptides are limited to local administration due to the intrinsic susceptibility against proteolysis. To address this, non-natural backbones have been designed to mimic AMP structures. With an engineered backbone based on oligo-N-substituted glycines, peptoids have been used to explore the potential utility as a novel anti-infective drug.
This presentation will cover the recent discovery of multi-target antimicrobial peptoids with potent activity and enhanced selectivity. 2,3 Our strategy of engaging multiple bacterial target sites offers significant potential for developing resistance-breaking novel antibiotics. In the later part of this talk, our recent efforts to establish structure-membrane permeability relationship using macrocyclic cyclosporine derivatives will be presented. 4,5
References
[1] Koo, H. B.; Seo, J. Peptide Science 2019, 111, e24122.
[2] Song, D. † ; Kim, B. † ; Kim, M. † ; Lee, J. K.; Choi, J.; Lee, H.; Shin, S.; Shin, D.; Nam, H. Y.; Lee, Y.; Lee, S.; Kim, Y.*; Seo, J.* Impact of conjugation of the reactive oxygen species (ROS)-generating catalytic moiety with membrane-active antimicrobial peptoids: Promoting multi-target mechanism and enhancing selectivity. J. Med. Chem. 2024, 67, 15148-15167
[3] Kim, M. † ; Cheon, Y. † ; Shin, D. † ; Choi, J.; Nielsen, J. E.; Jeong, M. S.; Nam, H. Y.; Kim, S. H.; Lund, R.; Jenssen, H.; Barron, A. E.; Lee, S.*; Seo, J.* Real-Time Monitoring of Multitarget Antimicrobial Mechanisms of Peptoids Using Label-Free Imaging with Optical Diffraction Tomography. Adv. Sci. 2023, 10, 2302483 ( † equal contribution)
[4] Lee, D.; Choi, J.; Yang, M.J.; Park, C-. J.; Seo, J.* Controlling the chameleonic behavior and membrane permeability of cyclosporine derivatives via backbone and side chain modifications. J. Med. Chem. 2023, 66, 13189-13204
[5] Lee, D.; Lee, S.; Choi, J.; Kang, J.-A.; Song, Y.-K.; Kim, M. J.; Shin, D. -S.; Bae, M. A.; Kim, Y.-C.; Park, S. -G.; Park, C. -J.*; Lee, K. -R.*; Choi, J. -H.*; Seo, J.* Interplay among conformation, intramolecular hydrogen bonds, and chameleonicity in the membrane permeability and cyclophilin A binding of macrocyclic peptide cyclosporin O derivatives. J. Med. Chem. 2021, 64, 8272-8286