英国弗朗西斯·克里克研究所Peter Cherepanov、美国哈佛医学院Alan N. Engelman等研究人员合作取得一项新成果。他们的最新工作解析了第二代HIV整合酶抑制剂作用和病毒抗性的结构基础。相关论文于2020年1月30日在线发表在《科学》杂志上。
Title: Structural basis of second-generation HIV integrase inhibitor action and viral resistance
Author: Nicola J. Cook, Wen Li, Dénes Berta, Magd Badaoui, Allison Ballandras-Colas, Andrea Nans, Abhay Kotecha, Edina Rosta, Alan N. Engelman, Peter Cherepanov
Issue&Volume: 2020/01/30
Abstract: AbstractDespite worldwide prescription, the mechanistic basis for superiority of second-generation HIV integrase (IN) strand transfer inhibitors (INSTIs) is poorly understood. We use single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near atomic resolution. Q148H/G140S amino acid substitutions in IN that pervade clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone, which are critical for antagonizing Q148H/G140S mutant virus. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this important class of anti-HIV/AIDS therapeutics.
DOI: 10.1126/science.aay4919
Source: https://science.sciencemag.org/content/early/2020/01/30/science.aay4919