Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor JTP-0157602
Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor JTP-0157602
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新型 HIV-1 非催化位点整合酶抑制剂的抗病毒活性和耐药性特征 JTP-0157602
DOI：
10.1128/jvi.01843-21
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发表时间：
2022
影响因子：
5.4
通讯作者：
Hayashi Hironori
中科院分区：
文献类型：
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作者：
Ohata Yoshitsugu;Tomonaga Mitsunori;Watanabe Yasuo;Tomura Keiko;Kimura Koji;Akaki Tatsuo;Adachi Kaoru;Kodama Eiichi N.;Matsuzaki Yuji;Hayashi Hironori
HIV-1整合酶（IN）是病毒复制的必需酶。非催化位点整合酶抑制剂（Non-catalytic site integrase inhibitors，NCINIs）是一类具有变构作用的HIV-1 IN抑制剂，是一类潜在的新型抗逆转录病毒药物。在这份报告中，我们发现了一种新的NCINI，JTP-0157602，具有原始支架。JTP-0157602对HIV-1表现出强效抗病毒活性，血清偏移90%有效浓度（EC 90）为138 nM，与FDA批准的IN链转移抑制剂（INSTI）相当。该化合物对多种具有IN多态性的重组病毒完全有效，包括IN多态性的热点氨基酸124/125。此外，JTP-0157602对具有INSTI相关耐药突变（包括INSTI临床研究中出现的多个取代）的广泛重组病毒保留了强效抗病毒活性。JTP-0157602的耐药性选择实验导致A128 T和T174 I突变的出现，这些突变位于IN的透镜上皮源性生长因子/p75结合口袋处。JTP-0157602主要在复制周期的晚期抑制HIV-1复制，并且在存在JTP-0157602的情况下，由HIV-1潜伏感染的Jurkat细胞再活化产生的HIV-1病毒粒子无感染性。这些结果表明JTP-0157602和类似物化合物可用于治疗HIV-1感染性疾病。重要非催化位点整合酶抑制剂（NCINIs）是变构的HIV-1整合酶（IN）抑制剂，与IN的透镜上皮衍生生长因子（LEDGF）/p75结合口袋结合。NCINI有望成为一类新的抗HIV-1药物。在这项研究中，我们提出了一种新的NCINI，JTP-0157602，它对广泛的HIV-1菌株具有IN多态性的有效活性。此外，JTP-0157602对IN链转移酶耐药突变显示出较强的抗病毒活性，表明JTP-0157602及其类似物是治疗HIV-1感染的潜在药物。结构模拟表明JTP-0157602与IN的LEDGF/p75结合口袋结合，体外诱导耐药的结果揭示了JTP-0157602对HIV-1的耐药机制。这些数据揭示了开发新的NCINIs，表现出对HIV-1的有效活性，广泛的IN多态性和多药耐药HIV-1变体。
HIV-1 integrase (IN) is an essential enzyme for viral replication. Non-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 IN inhibitors and a potential new class of antiretrovirals. In this report, we identified a novel NCINI, JTP-0157602, with an original scaffold. JTP-0157602 exhibited potent antiviral activity against HIV-1 and showed a serum-shifted 90% effective concentration (EC90) of 138 nM, which is comparable to those of the FDA-approved IN strand transfer inhibitors (INSTIs). This compound was fully potent against a wide range of recombinant viruses with IN polymorphisms, including amino acids 124/125, a hot spot of IN polymorphisms. In addition, JTP-0157602 retained potent antiviral activity against a broad panel of recombinant viruses with INSTI-related resistance mutations, including multiple substitutions that emerged in clinical studies of INSTIs. Resistance selection experiments of JTP-0157602 led to the emergence of A128T and T174I mutations, which are located at the lens epithelium-derived growth factor/p75 binding pocket of IN. JTP-0157602 inhibited HIV-1 replication mainly during the late phase of the replication cycle, and HIV-1 virions produced by reactivation from HIV-1 latently infected Jurkat cells in the presence of JTP-0157602 were noninfectious. These results suggest that JTP-0157602 and analog compounds can be used to treat HIV-1 infectious diseases.IMPORTANCENon-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 integrase (IN) inhibitors that bind to the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. NCINIs are expected to be a new class of anti-HIV-1 agents. In this study, we present a novel NCINI, JTP-0157602, which has potent activity against a broad range of HIV-1 strains with IN polymorphisms. Furthermore, JTP-0157602 shows strong antiviral activity against IN strand transfer inhibitor-resistant mutations, suggesting that JTP-0157602 and its analogs are potential agents for treating HIV-1 infections. Structural modeling indicated that JTP-0157602 binds to the LEDGF/p75 binding pocket of IN, and the results ofin vitroresistance induction revealed the JTP-0157602 resistance mechanism of HIV-1. These data shed light on developing novel NCINIs that exhibit potent activity against HIV-1 with broad IN polymorphisms and multidrug-resistant HIV-1 variants.