Strengths and weaknesses of an HIV drug Retroviruses replicate by inserting a copy of their RNA, which has been reverse transcribed into DNA, into the host genome. This process involves the intasome, a nucleoprotein complex comprising copies of the viral integrase bound at the ends of the viral DNA. HIV integrase strand-transfer inhibitors (INSTIs) stop HIV from replicating by blocking the viral integrase and are widely used in HIV treatment. Cook et al. describe structures of second-generation inhibitors bound to the simian immunodeficiency virus (SIV) intasome and to an intasome with integrase mutations known to cause drug resistance. Passos et al. describe the structures of the HIV intasome bound to a second-generation inhibitor and to developmental compounds that are promising drug leads. These structures show how mutations can cause subtle changes in the active site that affect drug binding, show the basis for the higher activity of later-generation inhibitors, and may guide development of better drugs. Science, this issue p. 806, p. 810 Single-particle cryo–electron microscopy shows how inhibitors that bind the intasome may allow the development of better drugs against HIV. Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo–electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in 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 that are critical for antagonizing viruses containing the Q148H and G140S mutations. 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 class of anti-HIV/AIDS therapeutics.

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第二代 HIV 整合酶抑制剂作用和病毒耐药性的结构基础

HIV 药物逆转录病毒的优势和劣势通过将已被逆转录成 DNA 的 RNA 副本插入宿主基因组来复制。这个过程涉及整合体，一种核蛋白复合物，包含结合在病毒 DNA 末端的病毒整合酶的拷贝。HIV 整合酶链转移抑制剂 (INSTI) 通过阻断病毒整合酶来阻止 HIV 复制，并广泛用于 HIV 治疗。库克等人。描述了与猿免疫缺陷病毒 (SIV) 整合体和具有已知导致耐药性的整合酶突变的整合体结合的第二代抑制剂的结构。帕索斯等人。描述了与第二代抑制剂结合的 HIV 整合体的结构以及与有希望的药物先导化合物的开发化合物。这些结构显示了突变如何导致活性位点发生微妙变化，从而影响药物结合，显示了下一代抑制剂更高活性的基础，并可能指导更好药物的开发。科学，本期第 3 页。806 页。810 单粒子低温电子显微镜显示了结合 intasome 的抑制剂如何能够开发出更好的抗 HIV 药物。尽管第二代 HIV 整合酶链转移抑制剂 (INSTI) 已在世界各地开具处方，但人们对这些药物优越性的机制基础知之甚少。我们使用单粒子低温电子显微镜来观察先进的 INSTI dolutegravir 和 bictegravir 在近原子分辨率下的作用模式。导致临床 INSTI 失败的整合酶中谷氨酰胺-148→组氨酸 (Q148H) 和甘氨酸-140→丝氨酸 (G140S) 氨基酸取代扰乱了酶活性位点中的最佳镁离子配位。第二代化合物的扩展化学支架介导与蛋白质骨架的相互作用，这对于拮抗含有 Q148H 和 G140S 突变的病毒至关重要。我们的研究结果表明，与镁离子的结合是 INSTI 药效团的根本弱点，该药团被病毒利用以产生抗药性，并为开发此类抗 HIV/AIDS 疗法提供了结构框架。第二代化合物的扩展化学支架介导与蛋白质骨架的相互作用，这对于拮抗含有 Q148H 和 G140S 突变的病毒至关重要。我们的研究结果表明，与镁离子的结合是 INSTI 药效团的根本弱点，该药团被病毒利用以产生抗药性，并为开发此类抗 HIV/AIDS 疗法提供了结构框架。第二代化合物的扩展化学支架介导与蛋白质骨架的相互作用，这对于拮抗含有 Q148H 和 G140S 突变的病毒至关重要。我们的研究结果表明，与镁离子的结合是 INSTI 药效团的根本弱点，该药团被病毒利用以产生抗药性，并为开发此类抗 HIV/AIDS 疗法提供了结构框架。