Allosteric integrase inhibitors (ALLINIs) bind to the lens epithelial-derived growth factor (LEDGF) pocket on HIV-1 integrase (IN) and possess potent antiviral effects. Rather than blocking proviral integration, ALLINIs trigger IN conformational changes that have catastrophic effects on viral maturation, rendering the virions assembled in the presence of ALLINIs noninfectious. A high-throughput screen for compounds that disrupt the IN·LEDGF interaction was executed, and extensive triage led to the identification of a t-butylsulfonamide series, as exemplified by 1. The chemical, biochemical, and virological characterization of this series revealed that 1 and its analogs produce an ALLINI-like phenotype through engagement of IN sites distinct from the LEDGF pocket. Key to demonstrating target engagement and differentiating this new series from the existing ALLINIs was the development of a fluorescence polarization probe of IN (FLIPPIN) based on the t-butylsulfonamide series. These findings further solidify the late antiviral mechanism of ALLINIs and point toward opportunities to develop structurally and mechanistically novel antiretroviral agents with unique resistance patterns.

中文翻译：

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发现具有抗逆转录病毒活性的独特的化学和机械类别构HIV-1整合酶抑制剂

变构整合酶抑制剂（ALLINIs）与HIV-1整合酶（IN）的晶状体上皮衍生生长因子（LEDGF）结合，并具有有效的抗病毒作用。ALLINIs不会阻断前病毒的整合，而是触发IN构象变化，这些构象变化对病毒成熟具有灾难性影响，使在ALLINIs存在下组装的病毒体无感染性。进行了破坏IN·LEDGF相互作用的化合物的高通量筛选，并且广泛分流导致鉴定了叔丁基磺酰胺系列，如1所示。该系列的化学，生化和病毒学特征表明1其类似物通过与LEDGF口袋不同的IN位点的结合产生类似ALLINI的表型。证明目标参与并使该新系列与现有ALLINI区别开来的关键是开发了基于叔丁基磺酰胺系列的IN荧光偏振探针（FLIPPIN）。这些发现进一步巩固了ALLINIs的晚期抗病毒机制，并指出了开发具有独特抗药性的结构和机制新颖的抗逆转录病毒药物的机会。