In multicellular organisms, a family of tightly regulated cell adhesion receptors called integrins mediates communication among cells and between cells and their extracellular matrices. Impaired regulation of integrins leads to many pathologies, which in the adult kidney include inflammatory, autoimmune and thrombotic disorders, making integrins important therapeutic targets. Indeed FDA-approved peptidomimetics, synthetic small molecules and monoclonal antibodies (mAbs) are being used to treat thrombotic and autoimmune diseases, and more recently, mAbs targeting ?V?3 have been shown to prevent atherosclerosis, diabetic nephropathy and systemic sclerosis in animal models. The anti-integrin peptidomimetics and synthetic small molecule drugs in current use are patterned after the prototypical integrin binding Arg-Gly-Aps motif in ligands. Their parenteral use has caused serious adverse outcomes in treated patients, and clinical trials using these ligand-mimetics as oral drugs to prevent thrombosis have failed due to unexpected patient death of paradoxical thrombosis. Subsequent biochemical and structural studies showed that these drugs act as partial agonists, i.e. they induce the conformational changes in the integrin produced by binding of physiologic macromolecular ligands. This partial agonism has contributed to the unexpected adverse outcomes seen in treated patients. Hence the need for a better understanding of structure- activity relationships in these receptors and for development of pure antagonists that lack the partial agonism of the ligand-mimetic compounds in current use. Our recently published studies generated during the current funding period identified an RGD-based pure antagonist and revealed the atomic basis for its unexpected mechanism of action. These studies, in addition to new preliminary data, provide a novel path for synthesis of anti-integrin drugs that lack partial agonism, and a basis for understanding structure-function relationships in integrins in more details. Capitalizing on these exciting new developments is the subject of this competing renewal application.

Public Health Relevance

Integrins are important therapeutic targets in view of their recognized pathogenic roles in many thrombotic, fibrotic and inflammatory diseases including heart attacks and acute and chronic inflammatory kidney disease. A few FDA-approved drugs currently used to treat acute coronary syndromes cause excessive bleeding in some patients, and oral forms of these drugs failed large clinical trials due to unexpected patient death. These adverse outcomes are due in part to the ability of existing drugs to inadvertently activate the target receptors they are meant to inactivate. We have identified biologics that inhibit the target receptors without activating it. This unexpected finding now provides the means for rational drug design of a new generation of effective and safer anti-integrin drugs. This proposal builds on our findings with a series of chemical, computational, biochemical and structural studies aimed at better understating of the biology of integrins and at developing new and safer drugs to address unmet medical needs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK088327-05A1
Application #
8887869
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Ketchum, Christian J
Project Start
2010-06-01
Project End
2018-08-31
Budget Start
2015-09-03
Budget End
2016-08-31
Support Year
5
Fiscal Year
2015
Total Cost
$253,971
Indirect Cost
$103,971
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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