Pre-steady state kinetic analysis of cyclobutyl derivatives of 2’-deoxyadenosine 5’-triphosphate as inhibitors of HIV-1 reverse transcriptase

• Type of Material: Article
• Authors: Jiae Kim, Yale University; Ligong Wang, Yale University; Yongfeng Li, Emory University; Kimberlynne D. Becnel, Emory University; Kathleen M. Frey, Yale University; Scott J. Garforth, Albert Einstein College of Medicine; Vinayaka R. Prasad, Albert Einstein College of Medicine; Raymond F Schinazi, Emory University; Dennis C Liotta, Emory University; Karen S. Anderson, Yale University
• Language: English
• Date: 2012-06-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2012.04.078
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 22
• Issue: 12
• Start Page: 4064
• End Page: 4067
• Grant/Funding Information: RFS is supported by CFAR NIH grant 2P30-AI-050409 and the Department of Veterans Affairs.; We would also like to thank the National Institutes of Health for support to GM49551 to K.S.A.
• Keywords: Pharmacology & Pharmacy; RESISTANCE; K65R; Science & Technology; Life Sciences & Biomedicine; Physical Sciences; HIV-1 RT; MUTATIONS; K65R mutant of RT; Chemistry; Chemistry, Organic; TENOFOVIR; Chemistry, Medicinal; Tenofovir; Pre-steady state kinetics; Cyclobutyl adenosine analogs
• Research Categories: Health Sciences, Immunology; Health Sciences, Pharmacology; Chemistry, General

Abstract

Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RTWT. The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RTWT. The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RTK65R. These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.