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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Kim, Jiae¹  Wang, Ligong¹  Li, Yongfeng²  Becnel, Kimberlynne D.²  Frey, Kathleen M.¹  Garforth, Scott J.³  Prasad, Vinayaka R.³  Schinazi, Raymond F.^4,5  Liotta, Dennis C.²  Anderson, Karen S.¹ 

[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

[2] Emory Univ, Dept Chem, Atlanta, GA 30322 USA

[3] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA

[4] Emory Univ, Sch Med, Dept Pediat, Ctr AIDS Res,Lab Biochem Pharmacol, Atlanta, GA 30322 USA

[5] Vet Affairs Med Ctr, New Haven, CT 06520 USA

关键词: HIV-1 RT;    Cyclobutyl adenosine analogs;    Tenofovir;    K65R mutant of RT;    Pre-steady state kinetics;   

DOI  :  10.1016/j.bmcl.2012.04.078

来源: Elsevier

【 摘 要 】

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. (C) 2012 Elsevier Ltd. All rights reserved.

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