Summary information and primary citation

7aig; DSSR-derived features in text and JSON formats
X-ray (2.95 Å)
Hiv-1 reverse transcriptase complex with DNA and l-glutamate tenofovir
Gu W, Martinez S, Nguyen H, Xu H, Herdewijn P, De Jonghe S, Das K (2021): "Tenofovir-Amino Acid Conjugates Act as Polymerase Substrates-Implications for Avoiding Cellular Phosphorylation in the Discovery of Nucleotide Analogues." J.Med.Chem., 64, 782-796. doi: 10.1021/acs.jmedchem.0c01747.
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.

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