3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

IMPLICATIONS OF THE THREE-DIMENSIONAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE FOR RESISTANCE TO ANTIVIRAL DRUGS

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:30 (abstract no. 29)

Edward Arnold¹, Christopher Tantillo¹, Paul Boyer², Jianping Ding¹ , Birgit M. Roy¹, Arthur D. Clark Jr.¹, Rudy Pauwels³, Koen Andries³, Paul A.J. Janssen³, John Mellors⁴, Nicholas Deacon⁵ and Stephen H. Hughes^2
1Center for Advanced Biotechnology and Medicine and Rutgers University Chemistry Department, Piscataway, NJ, USA; ²NCI-Frederick Cancer Research and Development Center, Frederick, MD, USA; ³Janssen Research Foundation, Beerse, Belgium; ⁴University· of Pittsburgh Medical Center, Pittsburgh, PA, USA; ⁵he Macfarlane Burnet Centre for Medical Research Limited, Fairfield, Victoria, Australia

The analysis of crystal structures of HIV-1 reverse transcriptase (RT) complexed with a nucleic acid template-primer substrate (Jacobo-Molina et al., Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6320-4) and with a nonnucleoside α-APA inhibitor (Ding et al., submitted) are yielding insights into mechanisms of resistance to RT inhibitors. The current resolution of these two structures has enabled us to formulate detailed hypotheses about the possible mechanisms of RT drug resistance (cf, Nanni et al., Persp. in Drug Discovery and Design, 1993 1:129-53; Tantillo, et al., Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6320-4). Structural and biochemical data suggest that most of the sites associated with nucleoside resistance mutations (NRM) are not directly participating. with dNTP binding. Instead, the mechanism of inhibition of NRM may be through indirect interactions with the template-primer substrate, which may affect the geometry of the dNTP binding site (Boyer, PL et al., Proc Natl Acad Sci U S A. 1994 May 24;91(11):4882-6). In contrast with the NRM, most of the residues involved in nonnucleoside resistance mutations could be in contact with this class of RT inhibitors. A mutation that has been consistently seen in AZT-treated patients, L210W (Deacon et al., unpublished), is located close to the T215Y mutation site in the RT structure. Modelling suggests that the interaction of the aromatic rings of these residues in the L210W/T215Y double mutant could indirectly affect the geometry of the dNTP-binding site and thereby alter the affinity of HIV-l RT for AZT triphosphate. An analysis of the locations of mutations that confer resistance to phosphonoformate (Mellors et al., unpublished) suggests that resistance to PFA may occur through a similar mechanism as with nucleoside analogs. We are pursuing the crystal structure determination of HIV-1 RT mutants to illuminate the structural basis of drug resistance.

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1994-08-02
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