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Tenofovir-Amino Acid Conjugates Act as Polymerase Substrates—Implications for Avoiding Cellular Phosphorylation in the Discovery of Nucleotide Analogues
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-23 , DOI: 10.1021/acs.jmedchem.0c01747 Weijie Gu 1, 2 , Sergio Martinez 1 , Hoai Nguyen 2 , Hongtao Xu 1 , Piet Herdewijn 2 , Steven De Jonghe 1 , Kalyan Das 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-23 , DOI: 10.1021/acs.jmedchem.0c01747 Weijie Gu 1, 2 , Sergio Martinez 1 , Hoai Nguyen 2 , Hongtao Xu 1 , Piet Herdewijn 2 , Steven De Jonghe 1 , Kalyan Das 1
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Nucleotide analogues are used for treating viral infections such as HIV, hepatitis B, hepatitis C, influenza, and SARS-CoV-2. To become polymerase substrates, a nucleotide analogue must be phosphorylated by cellular kinases which is rate-limiting. The goal of this study is to develop dNTP/NTP analogues directly from nucleotides. Tenofovir (TFV) analogues were synthesized by conjugating with amino acids. We demonstrate that some conjugates act as dNTP analogues and HIV-1 reverse transcriptase (RT) catalytically incorporates the TFV part as the chain terminator. X-ray structures in complex with HIV-1 RT/dsDNA showed binding of the conjugates at the polymerase active site, however, in different modes in the presence of Mg2+ versus Mn2+ ions. The adaptability of the compounds is seemingly essential for catalytic incorporation of TFV by RT. 4d with a carboxyl sidechain demonstrated the highest incorporation. 4e showed weak incorporation and rather behaved as a dNTP-competitive inhibitor. This result advocates the feasibility of designing NTP/dNTP analogues by chemical substitutions to nucleotide analogues.
中文翻译：
替诺福韦-氨基酸缀合物起聚合酶底物的作用—在发现核苷酸类似物时避免细胞磷酸化的意义。
核苷酸类似物用于治疗病毒感染，例如HIV，乙型肝炎，丙型肝炎，流行性感冒和SARS-CoV-2。为了成为聚合酶底物，核苷酸类似物必须被限速的细胞激酶磷酸化。这项研究的目的是直接从核苷酸开发dNTP / NTP类似物。替诺福韦（TFV）类似物通过与氨基酸结合而合成。我们证明，一些共轭物充当dNTP类似物和HIV-1逆转录酶（RT）催化纳入TFV部分作为链终止剂。与HIV-1 RT / dsDNA复合的X射线结构显示了结合物在聚合酶活性位点处的结合，但是，在存在Mg 2+与Mn 2+的情况下，其结合方式不同离子。化合物的适应性似乎是通过RT催化引入TFV所必需的。具有羧基侧链的4d表现出最高的结合。图4e显示弱结合，并且表现为dNTP竞争性抑制剂。该结果提倡通过化学取代核苷酸类似物来设计NTP / dNTP类似物的可行性。
更新日期：2021-01-14
中文翻译：
替诺福韦-氨基酸缀合物起聚合酶底物的作用—在发现核苷酸类似物时避免细胞磷酸化的意义。
核苷酸类似物用于治疗病毒感染，例如HIV，乙型肝炎，丙型肝炎，流行性感冒和SARS-CoV-2。为了成为聚合酶底物，核苷酸类似物必须被限速的细胞激酶磷酸化。这项研究的目的是直接从核苷酸开发dNTP / NTP类似物。替诺福韦（TFV）类似物通过与氨基酸结合而合成。我们证明，一些共轭物充当dNTP类似物和HIV-1逆转录酶（RT）催化纳入TFV部分作为链终止剂。与HIV-1 RT / dsDNA复合的X射线结构显示了结合物在聚合酶活性位点处的结合，但是，在存在Mg 2+与Mn 2+的情况下，其结合方式不同离子。化合物的适应性似乎是通过RT催化引入TFV所必需的。具有羧基侧链的4d表现出最高的结合。图4e显示弱结合，并且表现为dNTP竞争性抑制剂。该结果提倡通过化学取代核苷酸类似物来设计NTP / dNTP类似物的可行性。
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