A snake venom-analog peptide that inhibits SARS-CoV-2 and papain-like protease displays antithrombotic activity in mice arterial thrombosis model, without interfering with bleeding time

Thrombosis Journal

Research

Marina Rodrigues Pereira¹  Eduardo Maffud Cilli¹  Ruben Siedlarczyk Nogueira²  Bruno Ramos Salu²  Camila Ramalho Bonturi²  Maria Luiza Vilela Oliva²  Vinícius Goulart Nardelli²  Francisco Humberto de Abreu Maffei³ 

[1] Department of Biochemistry and Organic Chemistry, Institute of Chemistry, Universidade Estadual Paulista (UNESP), 14800-060, São Paulo, Araraquara, SP, Brazil;Department of Biochemistry, Universidade Federal de São Paulo (UNIFESP), 04044- 020, São Paulo, SP, Brazil;Department of Surgery and Orthopedics, Universidade Estadual Paulista (UNESP), 18618-687, São Paulo, Botucatu, SP, Brazil;

关键词: Bleeding;    COVID-19;    Cysteine-protease;    Papain-like protease;    Platelets;    SARS-CoV-2;    Thrombosis;   

DOI  :  10.1186/s12959-022-00436-5

 received in 2022-07-05, accepted in 2022-11-18,  发布年份 2022

来源: Springer

【 摘 要 】

Background(p-BthTX-I)2 K, a dimeric analog peptide derived from the C-terminal region of phospholipase A2-like bothropstoxin-I (p-BthTX-I), is resistant to plasma proteolysis and inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains with weak cytotoxic effects. Complications of SARS-CoV-2 infection include vascular problems and increased risk of thrombosis; therefore, studies to identify new drugs for treating SARS-CoV-2 infections that also inhibit thrombosis and minimize the risk of bleeding are required.ObjectivesTo determine whether (p-BthTX-I)2 K affects the hemostatic system.MethodsPlatelet aggregation was induced by collagen, arachidonic acid, and adenosine diphosphate (ADP) in the Chronolog Lumi-aggregometer. The coagulation activity was evaluated by determining activated partial thromboplastin clotting time (aPTT) and prothrombin time (PT) with (p-BthTX-I)2 K (5.0–434.5 µg) or 0.9% NaCl. Arterial thrombosis was induced with a 540 nm laser and 3.5–20 mg kg− 1 Rose Bengal in the carotid artery of male C57BL/6J mice using (p-BthTX-I)2 K. Bleeding time was determined in mouse tails immersed in saline at 37 °C after (p-BthTX-I)2 K (4.0 mg/kg and 8.0 mg/kg) or saline administration.Results(p-BthTX-I)2 K prolonged the aPTT and PT by blocking kallikrein and FXa-like activities. Moreover, (p-BthTX-I)2 K inhibited ADP-, collagen-, and arachidonic acid-induced platelet aggregation in a dose-dependent manner. Further, low concentrations of (p-BthTX-I)2 K extended the time to artery occlusion by the formed thrombus. However, (p-BthTX-I)2 K did not prolong the bleeding time in the mouse model of arterial thrombosis.ConclusionThese results demonstrate the antithrombotic activity of the peptide (p-BthTX-I)2 K possibly by kallikrein inhibition, suggesting its strong biotechnological potential.

【 授权许可】

CC BY   
© The Author(s) 2023

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