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 mu M) and plasma kallikrein (PKa; Ki: 28.54 mu M), two key enzymes in the contact-kinin system, surpassing the inhibitory effects of its linear form. In vitro, 4-100 mu M 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, FeCl3-induced arterial thrombosis, and cortical photothrombosis models, and did not affect mouse tail bleeding time. The peptide also exerted comparable anti-ischemic stroke effects to those of ecallantide (DX-88), a kallikrein inhibitor approved for the treatment of hereditary angioedema, in a mouse model of transient middle cerebral artery occlusion. Thus, this short peptide CycloSD6, which dual targets FXII and PKa, harbors anti-thromboinflammation and anti-stroke properties with low bleeding risk. And these findings suggest that cycloSD6 may serve as a potential therapeutic candidate or template for the development of agents targeting ischemic stroke.
[1]Henan Agr Univ, Coll Life Sci, Zhengzhou 450001, Henan, Peoples R China.
[2]Chinese Acad Sci, Engn Lab Peptides, Sino African Joint Res Ctr, Key Lab Bioact Peptides Yunnan Prov,KIZ CUHK Joint, 17 Longxin Rd, Kunming 650201, Yunnan, Peoples R China.
[3]Chinese Acad Sci, Kunming Inst Zool, 17 Longxin Rd, Kunming 650201, Yunnan, Peoples R China.
[4]Kunming Med Univ, Affiliated Hosp 1, Dept Anesthesiol, Kunming 650032, Yunnan, Peoples R China.
[5]Kunming Med Univ, Yanan Hosp, Kunming 650032, Yunnan, Peoples R China.
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