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人嗜T淋巴细胞病毒1型、2型和3型蛋白酶的生化特性、特异性及抑制研究

Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases.

作者信息

Kassay Norbert, Mótyán János András, Matúz Krisztina, Golda Mária, Tőzsér József

机构信息

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary.

出版信息

Life (Basel). 2021 Feb 6;11(2):127. doi: 10.3390/life11020127.

DOI:10.3390/life11020127
PMID:33562087
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7915765/
Abstract

The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1' subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.

摘要

人类嗜T淋巴细胞病毒（HTLVs）是包括成人T细胞白血病在内的严重疾病的病原体。与人类免疫缺陷病毒（HIVs）类似，病毒蛋白酶（PR）通过加工病毒多聚蛋白在病毒生命周期中发挥关键作用。因此，它是抗逆转录病毒疗法的潜在靶点。在本研究中，我们对1型、2型和3型人类T细胞白血病病毒（HTLV-1、-2和-3）蛋白酶进行了体外比较分析。通过使用一系列代表蛋白酶天然和修饰切割位点序列的合成寡肽底物，研究了S4至S1'亚位点的氨基酸偏好。还测定了不同PR的生化特性，包括催化效率以及活性对pH、温度和离子强度的依赖性。我们研究了不同的HIV-1 PR抑制剂（阿扎那韦、达芦那韦、DMP-323、茚地那韦、利托那韦和沙奎那韦）对酶活性的影响，以及先前针对HTLV-1 PR设计的IB-268和IB-269抑制剂的抑制潜力。对HTLV-1、-2和-3 PRs的比较生化分析可能有助于了解这些酶之间的特征异同，以便评估针对特定HTLV-1 PR抑制剂出现耐药性的可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2887/7915765/f5e0ab781549/life-11-00127-g011.jpg
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