The contact-kinin system plays a central role in the thromboinflammatory pathology of ischemic stroke. Modulating this pathway represents a promising strategy for the prevention and treatment of ischemic stroke. Based on our recent findings demonstrating that the short peptide SD6 (SLGASD), derived from a specific influenza-related immunoglobulin heavy chain junction region sequence, exhibits anti-coagulant properties, we designed a cyclized version, cycloSD6, and evaluated its anti-ischemic stroke potential. Notably, cycloSD6 showed enhanced inhibition of activated coagulation factor XII (FXIIa
with an inhibition constant (Ki) of 41.27 μM) and plasma kallikrein (PKa
Ki: 28.54 μM), two key enzymes in the contact-kinin system, surpassing the inhibitory effects of its linear form. In vitro, 4-100 μM of CycloSD6 inhibited LPS-induced inflammation. And CycloSD6 at doses of 1 and 4 mg/kg displayed significant anti-thrombotic functions in several mouse models, including carrageenan-induced tail thrombosis, FeCl