Hilimire Thomas A, Chamberlain Jeffrey M, Anokhina Viktoriya, Bennett Ryan P, Swart Oliver, Myers Jason R, Ashton John M, Stewart Ryan A, Featherston Aaron L, Gates Kathleen, Helms Eric D, Smith Harold C, Dewhurst Stephen, Miller Benjamin L
OyaGen, Inc. , Rochester, New York 14623, United States.
Department of Chemistry, SUNY Geneseo , Geneseo, New York 14454, United States.
ACS Chem Biol. 2017 Jun 16;12(6):1674-1682. doi: 10.1021/acschembio.7b00052. Epub 2017 May 5.
The HIV-1 frameshift-stimulating (FSS) RNA, a regulatory RNA of critical importance in the virus' life cycle, has been posited as a novel target for anti-HIV drug development. We report the synthesis and evaluation of triazole-containing compounds able to bind the FSS with high affinity and selectivity. Readily accessible synthetically, these compounds are less toxic than previously reported olefin congeners. We show for the first time that FSS-targeting compounds have antiviral activity against replication-competent HIV in human cells, including a highly cytopathic, multidrug-resistant strain. These results support the viability of the HIV-1 FSS RNA as a therapeutic target and more generally highlight opportunities for synthetic molecule-mediated interference with protein recoding in a wide range of organisms.
HIV-1移码刺激（FSS）RNA是一种在病毒生命周期中至关重要的调节性RNA，已被认为是抗HIV药物开发的新靶点。我们报告了能够以高亲和力和选择性结合FSS的含三唑化合物的合成与评估。这些化合物合成简便，毒性比先前报道的烯烃类似物低。我们首次表明，靶向FSS的化合物对人类细胞中具有复制能力的HIV具有抗病毒活性，包括一种高度致细胞病变的多药耐药菌株。这些结果支持将HIV-1 FSS RNA作为治疗靶点的可行性，更广泛地说，突出了合成分子介导干扰多种生物体中蛋白质重新编码的机会。
