STRUCTURE & FUNCTION ANALYSIS OF KAPOSIS SARCOMA ASSOCIATED PROTEASE: AIDS

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Kaposi's Sarcoma, a common AIDS-associated neoplasm, has been correlated with the infection and replication of a recently identified human herpesvirus (HHV-8). HHV-8, also known as Kaposi's sarcoma-associated herpesvirus (KSHV) requires the concerted activity of a virally-encoded protease (Pr) and its substrate, the assembly protein (AP). This protease appears to utilize structural and substrate recognition motifs quite different from other serine proteases, such as those of the chymotrypsin and subtilisin families. These latter classes of enzymes have been extensively studied by the Craik group; such previous knowledge should aid remarkably in the elucidation of the molecular details of KSHV Pr's assembly, structure, substrate recognition, and catalytic mechanism. Indeed, the active, purified enzyme now available in the Craik lab has led to promising initial advances in these areas. In addition, the relationship of this Pr to that of the commonly co-infected human immunodeficiency virus is being explored, and the rational design of small-molecule and dominant-negative inhibitors of the maturational activity of KSHV Pr will be pursued in an analogous fashion. In all these questions of enzyme structure, mechanism, and inhibitor design, the resources of the Computer Graphics Laboratory have proved an invaluable tool for developing pharmaceutical strategies to alleviate the progression of Kaposi's Sarcoma in AIDS patients.