使用氟硫酸弹头对野生型HIV-1逆转录酶进行共价抑制。
Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead.
作者信息
Ippolito Joseph A, Niu Haichan, Bertoletti Nicole, Carter Zachary J, Jin Shengyan, Spasov Krasimir A, Cisneros José A, Valhondo Margarita, Cutrona Kara J, Anderson Karen S, Jorgensen William L
机构信息
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
出版信息
ACS Med Chem Lett. 2021 Jan 6;12(2):249-255. doi: 10.1021/acsmedchemlett.0c00612. eCollection 2021 Feb 11.
Abstract
Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC values for in vitro inhibition of WT RT and EC values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.
摘要
有报道称发现了野生型HIV-1逆转录酶的共价抑制剂（CRTIs）。三种源自儿茶酚二醚非核苷抑制剂（NNRTIs）并添加了氟硫酸弹头的化合物被证明可共价修饰HIV-RT的Tyr181。提供了CRTIs与该酶复合物的X射线晶体结构，充分证明了共价结合，并且电喷雾飞行时间质谱（ESI-TOF）中的适当质量位移也证实了这一点。发现这三种CRTIs和六种非共价类似物都是强效抑制剂，其对野生型逆转录酶的体外抑制IC值以及对HIV-1感染的人类T细胞的细胞病变保护EC值均在5-320 nM范围内。
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