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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 12; pp. 4064 - 4067
• Main Authors: Kim, Jiae, Wang, Ligong, Li, Yongfeng, Becnel, Kimberlynne D., Frey, Kathleen M., Garforth, Scott J., Prasad, Vinayaka R., Schinazi, Raymond F., Liotta, Dennis C., Anderson, Karen S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.06.2012; Elsevier
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cyclobutanes - chemical synthesis; Cyclobutanes - pharmacology; Cyclobutyl adenosine analogs; Deoxyadenine Nucleotides - chemical synthesis; Deoxyadenine Nucleotides - pharmacology; DNA Primers; Drug Resistance, Viral - drug effects; Drug Resistance, Viral - genetics; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 RT; Humans; K65R mutant of RT; Kinetics; Medical sciences; Mutation; Nucleic Acid Amplification Techniques; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Pre-steady state kinetics; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; Tenofovir; Tenofovir; HIV-1 RT; Cyclobutyl adenosine analogs; Pre-steady state kinetics; K65R mutant of RT; Purine nucleoside; Antiretroviral agent; RNA-directed DNA polymerase; HIV-1 virus; Nucleotide analog; Phosphorus Organic compounds; Reverse transcriptase inhibitor; Nucleoside analog; Antiviral; Purine nucleotide; Adenosine; Acyclic nucleotide; Enzyme; Transferases; Retroviridae; Enzyme inhibitor; Organic phosphonate; Triphosphates; Lentivirus; Virus; Nucleotidyltransferases; Cyclobutane derivatives; Human immunodeficiency virus; Kinetics; Mutation; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.04.078

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.