2012 Fiscal Year Final Research Report
Design of synthetic agents that disrupt protein-protein interactions
| Project/Area Number |
22350074
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemistry related to living body
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| Research Institution | Osaka University |
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Principal Investigator |
OHKANDA Junko 大阪大学, 産業科学研究所, 准教授 (50233052)
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| Project Period (FY) |
2010 – 2012
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| Keywords | たんぱく質間相互作用 / 阻害剤 / 分子設計 / 金属錯体 / K-Ras / プレニル転移酵素 / 14-3-3 たんぱく質 |
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| Research Abstract |
Low-molecular-weight compounds that disrupt protein-protein interactions (PPIs) have tremendous potential applications as clinical agents and as chemical probes forinvestigating intracellular PPI networks. However, disrupting PPIs is extremely difficult due to the large, flat interfaces of many proteins, which often lack structurally defined cavities to which drug-like molecules could bind in a thermodynamically favorable manner. In this study, we examined the module-assembly strategy for designing PPI inhibitors, in which small module compounds are designed and assembled either by covalent linking with a linker, metal coordination, or chemical ligation on the targeted protein surface, to create a multivalent agent. For example, covalent linking of two modules designed for an active site and a PPI interface led to a potent bivalent agent that disrupt transient protein-protein interactions between protein prenyltransferases and K-Ras protein. These agents demonstrated significant inhibition activity against both farnesylation and geranylgeranylation of K-Ras C-terminal oligopeptide. Furthermore, structural modification by introducing guanidyl groups and peptidomimetics improved the cell permeation of agents, resulting in submicromolar inhibitors for FTase in cells.
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