Structure-Based De Novo Design of Mycobacterium Tuberculosis VapC-Activating Stapled Peptides
Structure-Based De Novo Design of Mycobacterium Tuberculosis VapC-Activating Stapled Peptides
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DOI：
10.1021/acschembio.0c00492
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发表时间：
2020-09-18
影响因子：
4
通讯作者：
Lee, Bong-Jin
中科院分区：
文献类型：
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作者：
Kang, Sung-Min;Moon, Heejo;Lee, Bong-Jin
毒素-抗毒素（TA）系统被认为是细菌生存的重要因素。在我们针对结核病（TB）的药物开发计划中，我们发现了某些模拟VapBC 30复合物结合的肽，导致细菌细胞生长停滞并最终导致细胞死亡。在此，我们基于烃钉合策略优化了这些候选肽，并进行了生物体外评价。V30-SP-8肽成功地穿透耻垢分枝杆菌细胞膜，并在抑制50%分离株（MIC 50）< 6.25 μ M的最小抑制浓度下发挥杀菌活性。借助M.结核病，我们提出了潜在的抗菌药物，可以提供一个平台，建立一个新的抗菌策略。由于靶向TA系统的治疗药物数量有限，我们相信这项研究不仅为探索与TA系统相关的生物学事件提供了化学工具，而且为结核病药物发现开辟了新的途径。
Toxinantitoxin (TA) systems have been considered essential factors for bacterial survival. During our drug development program aimed against tuberculosis (TB), we discovered certain peptides that mimic the binding of the VapBC30 complex, leading to the arrest of bacterial cell growth and eventually cell death. Herein, we optimized these candidate peptides based on a hydrocarbon stapling strategy and performed biological in vitro evaluations. The V30-SP-8 peptide successfully penetrated Mycobacterium smegmatis cell membranes and exerted bactericidal activity at a minimum inhibitory concentration that inhibited 50% of the isolates (MIC50) < 6.25 mu M. With the aid of structural and biochemical information for the VapBC30 TA system from M. tuberculosis, we suggest potential antimicrobial agents that could provide a platform to establish a novel antibacterial strategy. Reflecting the limited number of therapeutic agents targeting TA systems, we believe that this study not only provides chemical tools for exploring the biological events relevant to TA systems but also opens a new gateway toward TB drug discovery.