Homodimeric enzymes as drug targets

A2 Review article, Literature review, Systematic review


Internal Authors/Editors


Publication Details

List of Authors: Cardinale, Salo-Ahen, Ferrari, Ponterini, Cruciani, Carosati, Tochowicz, Mangani, Wade, Costi
Publisher: Bentham Science Publishers Ltd.
Publication year: 2010
Journal: Current Medicinal Chemistry
Journal acronym: Curr Med Chem
Volume number: 17
Issue number: 9
Start page: 826
End page: 846
ISSN: 1875-533X
eISSN: 1875-533X


Abstract

Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homo- and/or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulating protein 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 particular case of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionally obligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservation in active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Two main types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved in protein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitors of HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitors requires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo or after unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibition through interference in dimer stability. Several techniques for studying these complex phenomena will be presented.

Last updated on 2019-18-10 at 03:06