p15^gag Proteinase of Myeloblastosis Associated Virus: Specificity Studies with Substrate Based Inhibitors

Abstract

The key role of retrovirus-encoded proteinases in limited proteolysis of polyprotein precursors, a prerequisite of the formation of mature infectious virions, makes these enzymes attractive targets of specific inhibitors. A rational basis for the design of such inhibitors requires detailed knowledge of the proteinase-inhibitor interactions at the level of three-dimensional structures. Such data are available so far only for the HIV-1 proteinase whose crystal complexes with some inhibitors were subject of X-ray studies.¹ The absence of such information on the myeloblastosis associated virus (MAV) proteinase, another retroviral aspartate proteinase, together with the need of finding a tight-binding yet hydrophilic inhibitor for both X-ray studies and titration of its active site, led us to investigate the interactions of the proteinase with various classes of custom-synthesized inhibitors.