Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States.
Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota - Twin Cities, Minneapolis, Minnesota 55455, United States.
ACS Chem Biol. 2021 Mar 19;16(3):529-538. doi: 10.1021/acschembio.0c00975. Epub 2021 Feb 23.
Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that can cause severe paralytic neurologic disease and immune disorders as well as cancer. An estimated 20 million people worldwide are infected with HTLV-1, with prevalence reaching 30% in some parts of the world. In stark contrast to HIV-1, no direct acting antivirals (DAAs) exist against HTLV-1. The aspartyl protease of HTLV-1 is a dimer similar to that of HIV-1 and processes the viral polyprotein to permit viral maturation. We report that the FDA-approved HIV-1 protease inhibitor darunavir (DRV) inhibits the enzyme with 0.8 μM potency and provides a scaffold for drug design against HTLV-1. Analogs of DRV that we designed and synthesized achieved submicromolar inhibition against HTLV-1 protease and inhibited Gag processing in viral maturation assays and in a chronically HTLV-1 infected cell line. Cocrystal structures of these inhibitors with HTLV-1 protease highlight opportunities for future inhibitor design. Our results show promise toward developing highly potent HTLV-1 protease inhibitors as therapeutic agents against HTLV-1 infections.
人类 T 细胞嗜淋巴细胞病毒 1 型（HTLV-1）是一种逆转录病毒，可导致严重的瘫痪性神经疾病和免疫紊乱，以及癌症。据估计，全世界有 2000 万人感染了 HTLV-1，在世界某些地区，其流行率达到 30%。与 HIV-1 形成鲜明对比的是，目前还没有针对 HTLV-1 的直接作用抗病毒药物（DAAs）。HTLV-1 的天冬氨酰蛋白酶是一种类似于 HIV-1 的二聚体，可将病毒多蛋白加工成允许病毒成熟。我们报告称，已获 FDA 批准的 HIV-1 蛋白酶抑制剂达芦那韦（DRV）对该酶的抑制效力为 0.8μM，并为针对 HTLV-1 的药物设计提供了一个支架。我们设计和合成的 DRV 类似物对 HTLV-1 蛋白酶的抑制作用达到亚微摩尔水平，并在病毒成熟试验和慢性 HTLV-1 感染细胞系中抑制了 Gag 的加工。这些抑制剂与 HTLV-1 蛋白酶的共晶结构突出了未来抑制剂设计的机会。我们的研究结果显示，开发高效的 HTLV-1 蛋白酶抑制剂作为针对 HTLV-1 感染的治疗药物具有广阔的前景。
