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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Dehnadi, Abbas; Benedict Cosimi, A; Neal Smith, Rex et al. (2017) Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys. Nat Commun 8:13899
Camarata, Troy D; Weaver, Grant C; Vasilyev, Alexandr et al. (2015) Negative Regulation of TGF? Signaling by Stem Cell Antigen-1 Protects against Ischemic Acute Kidney Injury. PLoS One 10:e0129561
Wu, Qing; Zhang, Jiaojiao; Koh, Wonshill et al. (2015) Talin1 is required for cardiac Z-disk stabilization and endothelial integrity in zebrafish. FASEB J 29:4989-5005
Zhang, Jiaojiao; Yuan, Shipeng; Vasilyev, Aleksandr et al. (2015) The transcriptional coactivator Taz regulates proximodistal patterning of the pronephric tubule in zebrafish. Mech Dev 138 Pt 3:328-35
Rui, Xianliang; Mehrbod, Mehrdad; Van Agthoven, Johannes F et al. (2014) The ?-subunit regulates stability of the metal ion at the ligand-associated metal ion-binding site in ?3 integrins. J Biol Chem 289:23256-63
Van Agthoven, Johannes F; Xiong, Jian-Ping; Alonso, José Luis et al. (2014) Structural basis for pure antagonism of integrin ?V?3 by a high-affinity form of fibronectin. Nat Struct Mol Biol 21:383-8
Adair, Brian D; Altintas, Mehmet M; Möller, Clemens C et al. (2014) Structure of the kidney slit diaphragm adapter protein CD2-associated protein as determined with electron microscopy. J Am Soc Nephrol 25:1465-73
Palmyre, Aurélien; Lee, Jeongeun; Ryklin, Gennadiy et al. (2014) Collective epithelial migration drives kidney repair after acute injury. PLoS One 9:e101304
Mahalingam, Bhuvaneshwari; Van Agthoven, Johannes F; Xiong, Jian-Ping et al. (2014) Atomic basis for the species-specific inhibition of ?V integrins by monoclonal antibody 17E6 is revealed by the crystal structure of ?V?3 ectodomain-17E6 Fab complex. J Biol Chem 289:13801-9
Frohlich, Else M; Alonso, José Luis; Borenstein, Jeffrey T et al. (2013) Topographically-patterned porous membranes in a microfluidic device as an in vitro model of renal reabsorptive barriers. Lab Chip 13:2311-9

Showing the most recent 10 out of 12 publications