TOWARD A UNIVERSAL INHIBITOR OF RETROVIRAL PROTEASES - COMPARATIVE-ANALYSIS OF THE INTERACTIONS OF LP-130 COMPLEXED WITH PROTEASES FROM HIV-I, FIV, AND EIAV

One of the major problems encountered in antiviral therapy against AID S is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes incl ude, at structurally equivalent positions, amino acids identical to th ose found in drug-resistant forms of HIV-1 PR. The statine-based inhib itor LP-130 was found to be a universal, nanomolar-range inhibitor aga inst all tested retroviral PRs. We solved the crystal structures of LP -130 in complex with retroviral PRs from HIV-1. feline immunodeficienc y virus, and equine infectious anemia virus and compared the structure s to determine the differences in the interactions between the inhibit or and the active-site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor mole cules. The only exceptions are the different conformations of naphthyl alanine side chains at the P3/P3' positions, which might be responsibl e for the variation in the K-i, values. These findings indicate that s uccessful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformatio nal differences, despite the variations in the type of residues formin g the active site region. Although strong, specific interactions betwe en the ligand and the enzyme might improve the potency of the inhibito r, the absence of such interactions seems to favor the universality of the compound. Hence, the ability of potential anti-AIDS drugs to inhi bit multiple retroviral PRs might indicate their likelihood of not eli citing drug resistance. These studies may also contribute to the devel opment of a small-animal model for preclinical testing of antiviral co mpounds.