A Peptide Inhibitor of HIV-1 Reverse Transcriptase Using α, β- Dehydro Residues: A Structure-Based Computer Model

Abstract

HIV-1 reverse transcriptase (RT) is a key enzyme involved in the replication of the virus and is a potential target for therapeutic intervention following infection. Several drugs that inhibit the enzyme from acting have been discovered. These include nucleoside-analogue inhibitors such as AZT (zidovudine), ddl and ddC, and non-nucleoside inhibitors such as nevirapine and delavirdine. All of them, however have been found to be of limited clinical utility because the RT becomes rapidly resistant to them on account of point mutations in the enzyme. One way to partly overcome this limitation is to design an inhibitor that has interactions mainly with the backbone and the conserved residues of RT. Using a rational drug- design approach based on the high resolution X-ray crystal structure of the RT-nevirapine complex (1), and the specific design principles of peptides containing dehydro-Alanine (ΔAla) generated by our theoretical calculations, we present here the design of a peptide inhibitor of RT. Energy minimization and molecular modeling of the interaction of the designed pentapeptide with the nevirapine-binding site indicate that the inhibitor has 60% of its interactions with the conserved regions of RT as compared to 30% in the case of nevirapine, thus making it much less sensitive to mutations in the enzyme.