Rega Institute for Medical Research , 3000 Leuven , Belgium.
Department of Microbiology, Immunology and Transplantation , KU Leuven , 3000 Leuven , Belgium .
J Med Chem. 2019 Nov 14;62(21):9996-10002. doi: 10.1021/acs.jmedchem.9b01289. Epub 2019 Oct 25.
HIV-1 reverse transcriptase (RT) is an essential enzyme, targeting half of approved anti-AIDS drugs. While nucleoside RT inhibitors (NRTIs) are DNA chain terminators, the nucleotide-competing RT inhibitor (NcRTI) INDOPY-1 blocks dNTP binding to RT. Lack of structural information hindered INDOPY-1 improvement. Here we report the HIV-1 RT/DNA/INDOPY-1 crystal structure, revealing a unique mode of inhibitor binding at the polymerase active site without involving catalytic metal ions. The structure may enable new strategies for developing NcRTIs.
HIV-1 逆转录酶（RT）是一种必需的酶，靶向一半已批准的抗艾滋病药物。虽然核苷逆转录酶抑制剂（NRTIs）是 DNA 链终止剂，但核苷酸竞争型逆转录酶抑制剂（NcRTI）INDOPY-1 阻止 dNTP 与 RT 结合。缺乏结构信息阻碍了 INDOPY-1 的改进。在这里，我们报告了 HIV-1 RT/DNA/INDOPY-1 晶体结构，揭示了抑制剂在聚合酶活性位点结合的独特模式，而不涉及催化金属离子。该结构可能为开发 NcRTIs 提供新的策略。
