Drug discovery platform using stabilized low affinity conformation of integrins
Inventors: Timothy Springer, Can Xie, Bing Luo, Benoit Smagghe, Mehmet Sen
Invention Types: Research Tool
Research Areas: Immunology
Keywords: Drug Discovery, Method of Use, Small Molecule/DrugFor More Information Contact: Dietz, Ryan
Dr. Springer's lab discovered that the introduction of a disulfide bond into an integrin polypeptide by the substitution of at least one cysteine residue in the polypeptide permits stabilization of the integrin in a ''closed/inactive'' state. This stabilizing disulfide bond permits integrins to be screened for a candidate molecule that can bind to the closed state. In particular, this approach can be used to screen for agents that bind to the closed state of an integrin polypeptide, and are useful as therapeutic treatments to prevent integrin activation.|
Published patent #US 2010/0167418
• Identifying a candidate modulator of integrin activity, comprising of:
o contacting an integrin polypeptide with a candidate agent, wherein the integrin polypeptide is locked into a desired conformation.
o detecting binding of the candidate agent to the integrin polypeptide, wherein binding of the candidate agent to the integrin polypeptide is indicative that the candidate agent is a candidate modulator of integrin activity.
• The method of the candidate agent is selected from the group consisting of an antibody, a small molecule, a chemical, a peptide, and a peptidomimetic.
There is currently no known feature of integrin structure that would enable cytoskeleton binding to couple to the extended, open conformation with high affinity for ligand. This would appear to be important to fulfill the key role of integrins in integrating the extracellular and intracellular environments.
Key Publications: Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell. 2008 Dec 26;32(6):849-61. PubMed PMID: 19111664
IPStatus: Pat. Pend.