COMPARATIVE ANALYSIS OF THE INTERACTIONS OF AN INHIBITOR LP­130 COMPLEXED TO THREE RETROVIRAL PROTEASES

Alla Gustchina¹, Jukka Kervinen¹, Jacek Lubkowski¹, Alexander Zdanov¹, Deepa Bhatt², Ben M. Dunn², Kwan Y. Hui³, David J. Powell⁴, John Kay⁴ and Alexander Wlodawer¹

¹Macromolecular Structure Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA
²Department of Biochemistry and Molecular Biology, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610, USA
³Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
⁴School of Molecular and Medical Biosciences, University of Wales, Cardiff, P.O. Box 911, Cardiff, CF1 3US, Wales, United Kingdom

Keywords: Proteases, AIDS, drug design, drug resistance, retroviruses

One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include at structurally equivalent positions amino acids identical to those found in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130 was found to be a universal, nanomolar range inhibitor against all tested retroviral PRs. The crystal structures of LP-130 in complex with retroviral PRs from HIV-1, feline immunodeficiency virus, and equine infectious anemia virus were solved and compared in order to reveal the differences in the interactions between the inhibitor and the active site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor molecules. The only exceptions are the different conformations of naphthylalanine side chains at P3/P3' positions, which might be responsible for the variations in the K_i values. It indicates that successful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformational differences despite the variations in the type of the residues forming the active site region. While strong, specific interactions between the ligand and the enzyme might improve the potency of the inhibitor, their absence seems to favor the universality of the compound. Hence, the ability of potential AIDS drugs to inhibit multiple retroviral PRs may be a good indicator of their likelihood of not eliciting drug resistance. These studies may also contribute to the development of a small animal model for preclinical testing of antiviral compounds.