title: Module assembly for designing multivalent mid-sized inhibitors of protein-protein interactions.
abstract: Developing clinically relevant synthetic agents that are capable of disrupting protein-protein interactions (PPIs) is now a major goal of scientific research. In an effort to explore new methodologies that are applicable to the design of synthetic PPI inhibitors, we examined a strategy based on the assembly of small module compounds to create multivalent mid-sized agents. This personal account describes three particular approaches based on module assembly: metal-chelating-based ligand assembly, covalent chemical ligation templated by a targeted protein, and bivalent inhibitor design for simultaneous targeting of the active pocket and protein surface. These strategies were shown to be useful for synthesizing minimally sized synthetic agents for targeting PPIs and may enable development of agents that are applicable to inhibition of intracellular PPIs.
authors.affiliation: Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan. johkanda@scl.kyoto-u.ac.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D050091:Dendrimers / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D048948:14-3-3 Proteins; D050091:Dendrimers; D004791:Enzyme Inhibitors; D006027:Glycosides; D009942:Organometallic Compounds; C415768:tris(2,2'-bipyridyl)ruthenium(II); C007808:fusicoccin; D002918:Chymotrypsin; C117608:alpha-chymotrypsin
keywords: dual inhibitors; metal complexes; mid-sized molecules; protein-protein interactions; target-guided inhibitor synthesis