Zhao Xue Zhi, Smith Steven J, Maskell Daniel P, Metifiot Mathieu, Pye Valerie E, Fesen Katherine, Marchand Christophe, Pommier Yves, Cherepanov Peter, Hughes Stephen H, Burke Terrence R
Clare Hall Laboratories, The Francis Crick Institute , Blanche Lane, South Mimms, EN6 3LD, United Kingdom.
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
ACS Chem Biol. 2016 Apr 15;11(4):1074-81. doi: 10.1021/acschembio.5b00948. Epub 2016 Feb 5.
HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3'-processing and the bound host DNA prior to strand transfer. Using this concept of "bi-substrate mimicry," we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.
HIV整合酶（IN）链转移抑制剂（INSTIs）是最新的抗艾滋病药物之一；然而，IN的突变形式可导致耐药性。我们开发了含萘啶的无细胞毒性INSTIs，它们对携带所有主要INSTI耐药突变的HIV-1变体保持低纳摩尔IC50值。通过分析与原型泡沫病毒（PFV）的IN结合的抑制剂的晶体结构，我们发现最成功的抑制剂在3'-加工前对结合的病毒DNA以及链转移前对结合的宿主DNA表现出显著的模拟。利用这种“双底物模拟”概念，我们开发了一种新的广谱有效抑制剂，它不仅模拟结合的靶标和病毒DNA的各个方面，而且更完全地填充它们通常占据的空间。最大化形状互补性并概括包含IN的两个DNA底物的结构成分可作为开发新INSTIs的指导原则。
