2'-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants.

Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE

Publication: Oxford : Elsevier Science
Original Publication: Oxford : New York : Pergamon Press, c1993-

Reverse Transcriptase Inhibitors*/pharmacology ; Reverse Transcriptase Inhibitors*/chemistry ; Reverse Transcriptase Inhibitors*/chemical synthesis ; HIV Reverse Transcriptase*/antagonists & inhibitors ; HIV Reverse Transcriptase*/metabolism ; HIV-1*/drug effects ; Anti-HIV Agents*/pharmacology ; Anti-HIV Agents*/chemistry ; Anti-HIV Agents*/chemical synthesis ; Mutation*; Humans ; Structure-Activity Relationship ; Molecular Structure ; Nucleosides/chemistry ; Nucleosides/pharmacology ; Nucleosides/chemical synthesis ; Microbial Sensitivity Tests ; Dose-Response Relationship, Drug

Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3'-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2'-β-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3'-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3'-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

0 (Reverse Transcriptase Inhibitors)
EC 2.7.7.49 (HIV Reverse Transcriptase)
0 (Anti-HIV Agents)
0 (Nucleosides)
EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1)

Date Created: 20240702 Date Completed: 20240728 Latest Revision: 20240728

20240728

10.1016/j.bmc.2024.117813

38954919