Comparison of inhibitor binding to feline and human immunodeficiency virusproteases: Structure-based drug design and the resistance problem

The design and synthesis of compounds targeted against human immunodeficien cy virus I (HN-I) protease have resulted in effective antiviral therapies. However, the rapid replication of the virus and the inherent mutability of the viral genome result in the outgrowth of resistant strains in the majori ty of patients. Thus, there is a continuing need to develop new antiproteas e compounds that may bind more effectively to the resistant forms of protea se. This contribution enamines the binding of a single inhibitor to two dif ferent retroviral pretenses, HN-I protease and feline immunodeficiency viru s protease. Despite the overall similarity of the related retroviral enzyme s, specific substitutions within the binding site cavity provide a distinct ly different binding landscape that dramatically alters the affinity of com pounds. Through this comparison, insights have been obtained into new strat egies for drug design. New compounds based on these concepts have been rest ed against the two enzymes. (C) 1999 John Wiley & Sons, Inc.