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Antimicrobial Agents and Chemotherapy, November 2006, p. 3607-3614, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00537-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Chain-Terminating Dinucleoside Tetraphosphates Are Substrates for DNA Polymerization by Human Immunodeficiency Virus Type 1 Reverse Transcriptase with Increased Activity against Thymidine Analogue-Resistant Mutants{triangledown}

Peter R. Meyer,1 Anthony J. Smith,2 Suzanne E. Matsuura,1 and Walter A. Scott1,2*

Department of Biochemistry and Molecular Biology,1 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida2

Received 1 May 2006/ Returned for modification 15 June 2006/ Accepted 22 August 2006

Nucleoside reverse transcriptase inhibitors are an important class of drugs for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Resistance to these drugs is often the result of mutations that increase the transfer of chain-terminating nucleotides from blocked DNA termini to a nucleoside triphosphate acceptor, resulting in the generation of an unblocked DNA chain and synthesis of a dinucleoside polyphosphate containing the chain-terminating deoxynucleoside triphosphate analogue. We have synthesized and purified several dinucleoside tetraphosphates (ddAp4ddA, ddCp4ddC, ddGp4ddG, ddTp4ddT, Ap4ddG, 2'(3')-O-(N-methylanthraniloyl)-Ap4ddG, and AppNHppddG) and show that these compounds can serve as substrates for DNA chain elongation and termination resulting in inhibition of DNA synthesis. Thymidine analogue-resistant mutants of reverse transcriptase are up to 120-fold more sensitive to inhibition by these compounds than is wild-type enzyme. Drugs based on the dinucleoside tetraphosphate structure could delay or prevent the emergence of mutants with enhanced primer unblocking activity. In addition, such drugs could suppress the resistance phenotype of mutant HIV-1 that is present in individuals infected with resistant virus.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, P.O. Box 016129, Miami, FL 33101-6129. Phone: (305) 243-6359. Fax: (305) 243-3065. E-mail: wscott{at}med.miami.edu.

{triangledown} Published ahead of print on 28 August 2006.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3607-3614, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00537-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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