Chromatin Structure & Mobile DNA Laboratory, The Francis Crick Institute, London, United Kingdom.
Division of Infectious Diseases, School of Medicine, University of Colorado, Aurora, Colorado, USA.
mBio. 2023 Feb 28;14(1):e0356022. doi: 10.1128/mbio.03560-22. Epub 2023 Feb 6.
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD). Projecting from their principal binding pocket on the IN CCD dimer, the compounds act as molecular glue by engaging a triad of invariant HIV-1 IN CTD residues, namely, Tyr226, Trp235, and Lys266, to nucleate the CTD-CCD interaction. The drug-induced interface involves the CTD SH3-like fold and extends to the beginning of the IN carboxyl-terminal tail region. We show that mutations of HIV-1 IN CTD residues that participate in the interface with the CCD greatly reduce the IN-aggregation properties of Pirmitegravir. Our results explain the mechanism of the ALLINI-induced condensation of HIV-1 IN and provide a reliable template for the rational development of this series of antiretrovirals through the optimization of their key contacts with the viral target. Despite the remarkable success of combination antiretroviral therapy, HIV-1 remains among the major causes of human suffering and loss of life in poor and developing nations. To prevail in this drawn-out battle with the pandemic, it is essential to continue developing advanced antiviral agents to fight drug resistant HIV-1 variants. Allosteric integrase inhibitors (ALLINIs) are an emerging class of HIV-1 antagonists that are orthogonal to the current antiretroviral drugs. These small molecules act as highly specific molecular glue, which triggers the aggregation of HIV-1 integrase. In this work, we present high-resolution crystal structures that reveal the crucial interactions made by two potent ALLINIs, namely, BI-D and Pirmitegravir, with HIV-1 integrase. Our results explain the mechanism of drug action and will inform the development of this promising class of small molecules for future use in antiretroviral regimens.
变构 HIV-1 整合酶（IN）抑制剂（ALLINIs）是一类新兴的小分子，通过诱导 IN 的异常多聚化来破坏病毒成熟。在这里，我们展示了 HIV-1 IN 与两种强效 ALLINIs（即 BI-D 和候选药物 Pirmitegravir）的共晶结构。这些结构揭示了 ALLINI 诱导的 HIV-1 IN 催化核心和羧基末端结构域（CCD 和 CTD）之间界面的原子细节。从它们在 IN CCD 二聚体上的主要结合口袋伸出，化合物充当分子胶，通过与 HIV-1 IN CTD 的三个不变残基（Tyr226、Trp235 和 Lys266）结合，引发 CTD-CCD 相互作用。药物诱导的界面涉及 CTD SH3 样折叠，并延伸到 IN 羧基末端尾部区域的开始处。我们表明，参与与 CCD 界面的 HIV-1 IN CTD 残基的突变大大降低了 Pirmitegravir 诱导的 IN 聚集特性。我们的结果解释了 ALLINI 诱导的 HIV-1 IN 凝聚的机制，并为通过优化其与病毒靶标的关键接触来合理开发该系列抗逆转录病毒药物提供了可靠的模板。尽管联合抗逆转录病毒疗法取得了显著成功，但 HIV-1仍然是贫困和发展中国家人类痛苦和死亡的主要原因之一。要在这场与大流行的持久战中取得胜利，就必须继续开发先进的抗病毒药物来对抗耐药的 HIV-1 变异体。变构整合酶抑制剂（ALLINIs）是一类新兴的 HIV-1 拮抗剂，与当前的抗逆转录病毒药物不同。这些小分子作为高度特异性的分子胶，可触发 HIV-1 整合酶的聚集。在这项工作中，我们展示了高分辨率晶体结构，揭示了两种强效 ALLINIs（即 BI-D 和 Pirmitegravir）与 HIV-1 整合酶的关键相互作用。我们的结果解释了药物作用的机制，并将为这一有前途的小分子类别的开发提供信息，以用于未来的抗逆转录病毒方案。
