The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase

Cell Chemical Biology
Yuki TakamatsuKenji Maeda

Abstract

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA/MK-8591), a nucleoside reverse transcriptase inhibitor (NRTI) under clinical trials, is a potent and promising long-acting anti-HIV type 1 (HIV-1) agent. EFdA and its derivatives possess a modified 4'-moiety and potently inhibit the replication of a wide spectrum of HIV-1 strains resistant to existing NRTIs. Here, we report that EFdA and NRTIs with a 4'-ethynyl- or 4'-cyano-moiety exerted activity against HIV-1 with an M184V mutation and multiple NRTI-resistant HIV-1s, whereas NRTIs with other moieties (e.g., 4'-methyl) did not show this activity. Structural analysis indicated that EFdA and 4'-ethynyl-NRTIs (but not other 4'-modified NRTIs), formed strong van der Waals interactions with critical amino acid residues of reverse transcriptase. Such interactions were maintained even in the presence of a broad resistance-endowing M184V substitution, thus potently inhibiting drug-resistant HIV-1 strains. These findings also explain the mechanism for the potency of EFdA and provide insights for further design of anti-HIV-1 therapeutics.

Citations

Aug 20, 2019·Current Topics in Medicinal Chemistry·Kenji MaedaHiroaki Takeuchi
Jan 30, 2020·Expert Opinion on Investigational Drugs·Hanh Thi PhamThibault Mesplède
Jul 20, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Toshifumi TakeuchiFumio Sugawara
Apr 24, 2019·Pharmaceuticals·Kamal SinghAnders Sönnerborg
Apr 16, 2021·ACS Medicinal Chemistry Letters·Ei-Ichi Ami, Hiroshi Ohrui
Jan 26, 2022·Accounts of Chemical Research·Junbiao Chang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.