Homodimeric Enzymes as Drug Targets

Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homoand/or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulatingprotein function therapeutically. The large number of oligomeric structures in the Protein Data Bank (http://www.rcsb.org/) reflects growing interest in proteins that function as multimeric complexes. In this review, we consider the particularcase of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionallyobligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservationin active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Twomain types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved inprotein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitorsof HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitorsrequires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo orafter unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibitionthrough interference in dimer stability. Several techniques for studying these complex phenomena will be presented.