A unique biochemical target in the HIV-1 replication cyclewas revealed when HIV protease was cloned and expressedin Escherichia coli.HIV protease is an enzymethat cleaves gag-pro propeptides to yield active enzymesthat function in the maturation and propagation ofnew virus.The catalytically active protease is a symmetricdimer of two identical amino acid subunits, each contributingthe triad Asp-Thr-Gly to the active site. Most of the early PIs are high–molecular-weight,dipeptide-or tripeptide-like structures, generally with low watersolubility.The bioavailability of these compounds is low,and the half-life of elimination is very short because of hydrolysisor hepatic metabolism.Strategies aimed at in-creasing water solubility and metabolic stability have ledto the development of several highly promising clinicalcandidates.Saquinavir (Invirase),indinavir (Crixivan),ritonavir (Norvir),nelfinavir (Viracept),and amprenavir(Agenerase) have been approved for the treatmentof HIV-infected patients.Several others are in clinicaltrials. There is an important caution for the use of PIs.As aclass,they cause dyslipidemia, which includes elevated cholesteroland triglycerides and a redistribution of body fatcentrally to cause the “protease paunch” buffalo hump,facialatrophy, and breast enlargement. These agents alsocause hyperglycemia.
