A Cytoplasmic Template for the Development of Beta3 Drug Therapeutics

Abstract number: P0332

Haas TA

b₃ integrins on platelets (a_IIbb₃), cancer cells (a_Vb₃) and the endothelium (a_Vb₃) are targets for the treatment and prevention of cardiovascular diseases and cancer. a_IIbb₃, the fibrinogen receptor, is the central receptor in platelet aggregation. a_Vb₃ on angiogenic endothelial cells and tumor cells mediates diverse cellular responses including cell adhesion, migration, matrix reorganization, and metalloproteinase expression – processes central to metastasis and angiogenesis. Current b₃ therapeutics work by blocking the integrin's extracellular ligand-binding site. However, the efficacies of these drugs are limited to specific clinical settings, and thus there is a need for better integrin-based therapeutics. Here, I report that a region in the a cytoplasmic tails of b₃ integrins can block integrin activation. Using a number of truncated linear and cyclic peptides, the minimal sequence required for the inhibitory effect of a cytoplasmic peptides was localized to the conserved turn-motif. A critical residue for the inhibitory capacity in the a_V cytoplasmic peptides was identified, a_V(Q1001). The inhibition was activation-dependent, required peptide internalization, and was not due to a decrease in integrin surface expression. Their mode-of-action did not appear to be related to perturbing the a/b cytoplasmic interface, but rather by disrupting the connection between b₃ and scr kinase signalling molecules. These findings further our basic understanding of integrin signalling and may lead to the generation of a new class of anti-thrombotic, anti-angiogenic and anti-metastatic drugs.