Comparison of inhibitor binding to feline and human immunodeficiency virus proteases: structure-based drug design and the resistance problem.
The design and synthesis of compounds targeted against human immunodeficiency virus 1 (HIV-1) 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 majority of patients. Thus, there is a continuing need to develop new antiprotease compounds that may bind more effectively to the resistant forms of protease. This contribution examines the binding of a single inhibitor to two different retroviral proteases, HIV-1 protease and feline immunodeficiency virus protease. Despite the overall similarity of the related retroviral enzymes, specific substitutions within the binding site cavity provide a distinctly different binding landscape that dramatically alters the affinity of compounds. Through this comparison, insights have been obtained into new strategies for drug design. New compounds based on these concepts have been tested against the two enzymes.
Dunn
B M
BM
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville 32610-0245, USA. bdunn@college.med.ufl.edu
Pennington
M W
MW
Frase
D C
DC
Nash
K
K
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002415:Cats; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000201:enzymology*; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary
D017320:HIV Protease Inhibitors; D010455:Peptides; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C095555:FIV protease; D016333:HIV Protease