基于水分不敏感的快速NCA聚合反应探索抗真菌α-氨基酸聚合物

临床耐药性真菌感染不断出现，严重威胁人类健康和生命。针对目前抗真菌药物细胞选择性差、种类极其有限且易产生耐药问题等严峻挑战，本项目拟以α-氨基酸聚合物模拟宿主防御肽（HDP）获得高活性、低细胞毒性、低耐药性风险的抗真菌化合物。α-氨基酸N-羧基环内酸酐（NCA）开环聚合是制备氨基酸聚合物最常用方法，但是对水分超级敏感，需超干溶剂和手套箱等设备进行严格无水操作。本项目以申请人近期发现的六甲基二硅基胺基锂（LiHMDS）引发、对水分耐受的超快速NCA开环聚合为基础，通过系统、深入研究NCA聚合条件和反应机理，建立适用于多种氨基酸NCA的优化聚合方法，快速制备α-氨基酸聚合物并进行活性筛选和结构优化。预期发现具有高活性、高选择性、不易使真菌获得耐药性的抗真菌α-氨基酸聚合物并探究抗真菌机理。

Fungal infections threaten the health and lives of human beings, especially with the quick emergence of drug-resistant fungi. To address the grand challenge of poor selectivity, limited choice and susceptible to antimicrobial resistance of current antifungal drugs, this project will utilize α-amino acid polymers to mimic the host defense peptide (HDP) and find antifungal compounds with potent activity, low cytotoxicity and low propensity of antimicrobial resistance. Ring-opening polymerization of α-amino acid N-carboxyanhydride (NCA) is the most widely used synthesis of polypeptides. However, this reaction is super sensitive to water and generally needs to be conducted using dry solvent in a glovebox. Recently, we discovered a water insensitive and superfast NCA polymerization method using lithium bis(trimethylsilyl)amide (LiHMDS) as the initiator, which provides a starting point for our systematic and in-depth study on NCA polymerization conditions and reaction mechanism in this project to establish the optimum NCA polymerization conditions for diverse amino acid NCAs. We expect to obtain antifungal polypeptides with potent activity, excellent selectivity and low susceptibility to antimicrobial resistance. We will also explore the antifungal mechanism of these polypeptides.