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J. Biol. Chem., Vol. 278, Issue 21, 18971-18979, May 23, 2003

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Dioxolane Guanosine 5'-Triphosphate, an Alternative Substrate Inhibitor of Wild-type and Mutant HIV-1 Reverse Transcriptase

STEADY STATE AND PRE-STEADY STATE KINETIC ANALYSES^*

Jerry L. Jeffrey   ¶, Joy Y. Feng   ||, C. C. Richard Qi  **, Karen S. Anderson  and Phillip A. Furman  

From the Triangle Pharmaceuticals, Inc., a subsidiary of Gilead Sciences, Durham, North Carolina 27717, Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

The frequency of human immunodeficiency virus, type 1 (HIV-1) mutations in response to antiviral therapy and resulting drug resistance is of major concern. Amdoxovir ((–)--D-2,6-diaminopurine dioxolane), the prodrug of dioxolane guanosine (DXG), is currently in phase I/II clinical development for the treatment of HIV-1 infection. In vitro, HIV-1 mutants resistant to 3'-azido-3'-deoxythymidine (M41L/D67N/K70R/T215Y/K219Q) and (–)-L-2',3'-dideoxy-3'-thiacytidine (3TC) (M184V) remain sensitive to DXG. HIV-1 with the reverse transcriptase mutations K65R, L74V, and/or Q151M were less sensitive to DXG, whereas the mutation K103N re-sensitized the virus to the inhibitory effect of DXG. In order to understand these observations at the enzyme level, we investigated the inhibition of the HIV-1 reverse transcriptase-catalyzed viral DNA synthesis by dioxolane guanosine 5'-triphosphate (DXG-TP), 3'-azido-3'-deoxythymidine-TP, and 3TC-TP by using steady state kinetic analysis and the incorporation of DXG-5'-monophosphate by using pre-steady state kinetic analysis. This mechanistic study provided detailed information on the amdoxovir-related drug resistance at a molecular level. Overall, the enzymatic data correlated well with the antiviral data obtained from cell culture experiments and further supported the use of amdoxovir for the treatment of nucleoside reverse transcriptase inhibitor-experienced patients.

Received for publication, October 2, 2002 , and in revised form, March 20, 2003.

^|| To whom correspondence should be addressed: Triangle Pharmaceuticals, Inc., a subsidiary of Gilead Sciences, 4611 University Dr., P. O. Box 50530, Durham, NC 27717. Tel.: 919-402-2467; Fax: 919-493-5790; E-mail: joy.feng{at}gilead.com.

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