Integrins are a/ heterodimeric cell adhesion receptors that play essential roles in the developing and adult kidney, through tightly regulated metal-dependent interactions with the extracellular matrix (ECM) that modulate cell migration, proliferation, differentiation, matrix deposition and remodeling. Attempts to block integrins with current ligand-mimetic drugs, have been disappointing, as ligation of the integrin by these drugs stabilizes the receptor in the active conformation, enabling it to trigger outside in signaling, as with natural ligands, leading to paradoxical cell adhesion and mortality. I have recently determined the crystal structure of aV3 in complex with a macromolecular ligand selected for its high affinity and selectivity for this integrin. Unexpectedly, the new structure elucidated novl features of ligand-integrin interactions in which the ligand simultaneously binds but blocks outside-in signaling of the integrin.
My aims i n this proposal are to use this exciting result to carry-out structure-activity studies leading to design of pure integrin antagonists, and test the renoprotective effect of one of these ligand-mimetics in an established murine model of proteinuria.
The work proposed here will provide a basis for structure-based design and establish utility of integrin antagonists that do not elicit paradoxical cell adhesion, a detrimental outcome with use of existing integrin antagonists. It will specifically provide the therapeutical benefit of a pure antagonist of integrin aV3 evaluated in vitro and in vivo on an established proteinuric animal model.
