title: A Novel Direct Factor Xa Inhibitory Peptide with Anti-Platelet Aggregation Activity from Agkistrodon acutus Venom Hydrolysates.
abstract: Snake venom is a natural substance that contains numerous bioactive proteins and peptides, nearly all of which have been identified over the last several decades. In this study, we subjected snake venom to enzymatic hydrolysis to identify previously unreported bioactive peptides. The novel peptide ACH-11 with the sequence LTFPRIVFVLG was identified with both FXa inhibition and anti-platelet aggregation activities. ACH-11 inhibited the catalytic function of FXa towards its substrate S-2222 via a mixed model with a Ki value of 9.02 μM and inhibited platelet aggregation induced by ADP and U46619 in a dose-dependent manner. Furthermore, ACH-11 exhibited potent antithrombotic activity in vivo. It reduced paralysis and death in an acute pulmonary thrombosis model by 90% and attenuated thrombosis weight in an arterio-venous shunt thrombosis model by 57.91%, both at a dose of 3 mg/kg. Additionally, a tail cutting bleeding time assay revealed that ACH-11 did not prolong bleeding time in mice at a dose of 3 mg/kg. Together, our results reveal that ACH-11 is a novel antithrombotic peptide exhibiting both FXa inhibition and anti-platelet aggregation activities, with a low bleeding risk. We believe that it could be a candidate or lead compound for new antithrombotic drug development.
authors.affiliation: School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
authors.forename: Meimei
authors.initials: M
authors.lastname: Chen
authors.affiliation: School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ye
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Ming
authors.affiliation: School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
authors.forename: Xingli
authors.initials: X
authors.lastname: Su
authors.affiliation: School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.affiliation: 1] School of Life Science &Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, PR China [2] State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D017836:Agkistrodon / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D012910:Snake Venoms / Q000737:chemistry / Q000378:metabolism*; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D012910:Snake Venoms; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid