Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
Bioorg Med Chem. 2013 Oct 1;21(19):5963-72. doi: 10.1016/j.bmc.2013.07.047. Epub 2013 Aug 2.
Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase-LEDGF/p75 interaction in vitro. Following a structure-activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound's structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency.
尽管在抑制 HIV-1 整合酶催化方面已经取得了很大进展，但临床耐药突变限制了长期药物处方的前景。因此，整合酶活性的变构抑制已成为抗逆转录病毒发现和开发的一种有前途的方法。具体而言，已验证 HIV-1 整合酶与细胞辅助因子 LEDGF/p75 之间相互作用的抑制剂可减少前病毒整合并有效降低病毒复制能力。在这里，我们通过高通量基于 AlphaScreen 的随机筛选方法为新型变构整合酶抑制剂的开发做出了贡献，我们通过该方法鉴定出了新型的 5-羰基-1H-咪唑-4-甲酰胺，它们能够在体外抑制 HIV-1 整合酶-LEDGF/p75 相互作用。在对初始 1H-咪唑-4,5-二羰基核心进行构效关系分析后，我们通过工业数据库搜索对化合物结构进行了优化，并进一步合成了一组具有增强效力的选择性和非细胞毒性抑制剂。
