4'-Acylated thymidine 5'-triphosphates: a tool to increase selectivity towards HIV-1 reverse transcriptase.
4'-Acylated thymidines represent a new class of DNA chain terminators, since they have been shown to act as post-incorporation chain-terminating nucleotides despite the presence of a free 3'-hydroxyl group. Here, we describe the action of the 4'-acetyl- (MeTTP) and 4'-propanoylthymidine 5'-triphosphate (EtTTP) on HIV-1 reverse transcriptase in RNA- and DNA-dependent DNA synthesis and on DNA synthesis catalyzed by the cellular DNA polymerases alpha, beta, delta and epsilon. MeTTP exhibits a high selectivity towards HIV-1 reverse transcriptase. By the use of the bulkier propanoyl group as the 4'-substituent of the nucleoside 5'-triphosphate, selectivity towards HIV-1 reverse transcriptase could be increased without affecting substrate efficiency. Thus, 4'-modifications may serve as a tool to increase selectivity towards HIV-1 reverse transcriptase.
Marx
A
A
Department of Chemistry, University of Basel, St Johanns-Ring 19, CH-4056 Basel, Switzerland.
Amacker
M
M
Stucki
M
M
Hübscher
U
U
Bickle
T A
TA
Giese
B
B
D000215:Acylation; D019380:Anti-HIV Agents / Q000494:pharmacology; D017931:DNA Primers / Q000378:metabolism; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D009843:Oligoribonucleotides / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013942:Thymine Nucleotides / Q000494:pharmacology*
C114770:4'-acetylthymidine 5'-triphosphate; C114771:4'-propanoylthymidine triphosphate; D019380:Anti-HIV Agents; D017931:DNA Primers; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides; D009843:Oligoribonucleotides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; D054303:HIV Reverse Transcriptase