A peptide inhibitor of HIV-1 protease using alpha,beta-dehydro residues: Astructure based computer model

HIV-1 encodes an aspartic protease. an enzyme crucial to viral maturation a nd infectivity. It is responsible for the cleavage of various protein precu rsors into viral proteins. Inhibition of this enzyme prevents the formation of mature, infective viral particles and therefore, it is a potential targ et for therapeutic intervention following infection. Several drugs that inh ibit the action of this enzyme have been discovered. These include peptidom imetic inhibitors such as ABT-538 and saquinavir, and structure based inhib itors such as indinavir and nelfinavir. Several of these have been tested i n human clinical trials and have demonstrated significant reduction in vira l load. However, most of them have been found to be of limited clinical uti lity because of their poor pharmacological properties and also because the viral protease becomes rapidly resistant to these drugs on account of mutat ions in the enzyme. One way to overcome these limitations is to design an i nhibitor that interacts mainly with the conserved residues of HIV-I proteas e. By a rational drug design approach based on the high resolution X-ray cr ystal structure of the HIV-1 protease with - MVT 101 (a substrate based inh ibitor) and the specific design principles of peptides containing dehydro-A lanine (Delta Ala) derived from our earlier studies, we have designed a tet rapeptide with the sequence: NH2-Thr-Delta Ala-Delta Ala-Gln-COOH. Energy m inimization and molecular modelling of the interaction of the designed tetr apeptide with the inhibitor binding site indicate that the inhibitor is in an extended conformation and makes excessive contacts with the viral enzyme at the interface between the protein subunits. The designed inhibitor has 33% of its interaction with the conserved region of HIV-1 protease which is of the same order as that of MVT 101 with the enzyme.