1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

COMPARATIVE STRUCTURAL ANALYSIS OF INHIBITOR COMPLEXES OF WILD-TYPE AND DRUG-RESISTANT HIV-1 PROTEASE MUTANTS: IS A PATTERN EMERGING?

Antiviral Therapy 1997;2 (Suppl 5):20 (abstract no. 31)

John W Erickson, TN Bhat, R Randad, S Gulnik and B Yu
NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

Resistance to HIV-1 protease inhibitors is generally associated with the acquisition of one or more mutations in the active site of the enzyme upon prolonged exposure to drug. Initial studies on the structural effects of drug resistance-conferring mutations on inhibitor-enzyme interactions revealed a complex and idiosyncratic assortment of structural, electronic and solvation changes that can contribute to changes in the K_i, or free energy of binding, of an inhibitor with a particular mutant enzyme. However, comparative analysis of crystal structures of wild-type and drug-resistant mutant HIV-1 proteases complexed with a variety of inhibitors has led to an emerging understanding of the factors that govern the differential effects of mutations on drug binding affinity. Results of structural and biochemical studies will be presented that illustrate some of these principles and suggest strategies for the design of ‘resistance repellent’ inhibitors.

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1997-06-25
31

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