Design of Protease Inhibitors to Target HTLV-1

靶向HTLV-1的蛋白酶抑制剂的设计 人类T细胞白血病病毒1型（HTLV-1）是第一个被鉴定的感染人类T细胞白血病的逆转录病毒。 全世界数百万人。HTLV-1具有高度致癌性，感染可导致生命- 威胁癌症和致残性炎症。最近在澳大利亚爆发的一场大规模疫情， 在地球仪上持续感染人群，并传播到非流行地区， 移民局敦促立即采取行动解决这一基本上被忽视的疾病。近日 全球病毒网络工作组领导强烈建议扩大对以下方面的研究： HTLV-1。与高度相关的HIV-1形成鲜明对比的是，没有直接作用的抗病毒（DAA）药物 自从40年前发现HTLV-1以来，已经开发了针对HTLV-1的药物。 尽管酶促相似，但HTLV-1蛋白酶底物特异性与 HIV-1蛋白酶。这使得目前的HIV-1蛋白酶抑制剂不能有效地对抗 HTLV-1，尽管有些具有非常弱的结合。设计针对底物的抑制剂 HTLV-1蛋白酶的包膜代表了开发高效且 强效HTLV-1抑制剂。基质包层的表征还将揭示 高度被忽视的HTLV-1蛋白酶底物特异性的分子基础。翻译 我们的战略加上我们在HIV-1方面的丰富经验，将极大地造福于 发现针对HTLV-1的小分子抑制剂。

Design of Protease Inhibitors to Target HTLV-1 Human T cell leukemia virus type 1 (HTLV-1) is the first identified human retrovirus that infects millions of people worldwide. HTLV-1 is highly carcinogenic, and infection can lead to life- threatening cancers and disabling inflammatory conditions. A recent major outbreak in Australia, persistent infected populations over the globe, and spread to non-endemic regions with immigration urges immediate action to address this largely neglected disease. Recently, the Global Virus Network Task Force leadership has strongly recommended expanding research on HTLV-1. In stark contrast to the highly related HIV-1, no direct-acting antiviral (DAA) agents have been developed to target HTLV-1 since its discovery almost 40 years ago. Although enzymatically similar, the HTLV-1 protease substrate specificity is quite distinct from HIV-1 protease. This prevents the current HIV-1 protease inhibitors from being effective against HTLV-1, although some have very weak binding. Designing inhibitors to target the substrate envelope of HTLV-1 protease represents the best opportunity for developing a highly potent and robust HTLV-1 inhibitor. Characterization of the substrate envelope will also reveal the molecular basis of substrate specificity for the highly neglected HTLV-1 protease. Translation of our strategies coupled with our extensive experience with HIV-1 will immensely benefit the discovery of small molecule inhibitors against HTLV-1.