Your browser doesn't support javascript.
Tenofovir-Amino Acid Conjugates Act as Polymerase Substrates-Implications for Avoiding Cellular Phosphorylation in the Discovery of Nucleotide Analogues.
Gu, Weijie; Martinez, Sergio; Nguyen, Hoai; Xu, Hongtao; Herdewijn, Piet; De Jonghe, Steven; Das, Kalyan.
  • Gu W; KU Leuven, Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium.
  • Martinez S; KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium.
  • Nguyen H; KU Leuven, Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium.
  • Xu H; KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium.
  • Herdewijn P; KU Leuven, Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium.
  • De Jonghe S; KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium.
  • Das K; KU Leuven, Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium.
J Med Chem ; 64(1): 782-796, 2021 01 14.
Article in English | MEDLINE | ID: covidwho-997766
ABSTRACT
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Diseases / Tenofovir / Amino Acids / Nucleotides Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.0c01747

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Diseases / Tenofovir / Amino Acids / Nucleotides Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.0c01747