title: A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to IntegrinαIIbβ3.
abstract: IntegrinαIIbβ3 plays a crucial role in the process of platelet aggregation. Three integrinαIIbβ3 antagonists (abciximab, eptifibatide, and tirofiban) have been approved by FDA for clinical use. Unfortunately, they all showed severe side effects such as thrombocytopenia and bleeding risk. Thus, researches on the development of more effective and safer antiplatelet agents are needed. In this manuscript we reported a novel naphthalenic derivative compound ND-1 with potent antithrombotic effect and lower bleeding risk. ND-1 inhibited ADP-, collagen-, thrombin-, and U46619-induced platelet aggregation with IC50values of 1.29, 14.46, 12.84, and 40.24μM, respectively. Mechanism studies indicated that ND-1 inhibited the binding of fibrinogen to integrinαIIbβ3 in a dose-dependent manner with an IC50value of 3.12μM. ND-1 inhibited P-selectin expression induced by ADP, collagen, thrombin, and U46619 on the surface of platelets. Additionally, this compound reduced platelets spreading to the immobilized fibrinogen. In vivo, ND-1 potently decreased thrombus formation in an arteriovenous shunt thrombosis model in rats and slightly prolonged bleeding time in a tail cutting model in mice. Taken together, our results reveal that ND-1 is a novel antagonist ofαIIbβ3 with strong antithrombotic effect and lower bleeding risk.
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Ding
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Tong-Dan
authors.initials: TD
authors.lastname: Liu
authors.affiliation: School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Zhou-Ling
authors.initials: ZL
authors.lastname: Xie
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Cai-Hui
authors.initials: CH
authors.lastname: Wang
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Rwibasira Rudinga
authors.initials: RR
authors.lastname: Gamariel
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Xin
authors.identifier: 0000-0001-8368-250X
authors.initials: X
authors.lastname: Ming
authors.affiliation: School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Zhi-Yu
authors.identifier: 0000-0002-5343-3374
authors.initials: ZY
authors.lastname: Li
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Street, Nanjing 210009, China.
authors.forename: Yi
authors.identifier: 0000-0002-2329-7009
authors.initials: Y
authors.lastname: Kong
mesh_terms: D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D000077542:Eptifibatide; D005340:Fibrinogen / Q000378:metabolism*; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000627:therapeutic use; D039421:Integrin alpha2 / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism*; D051379:Mice; D009281:Naphthalenes / Q000008:administration & dosage*; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D013921:Thrombocytopenia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology; D000077466:Tirofiban; D014443:Tyrosine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D039421:Integrin alpha2; D039661:Integrin beta3; D009281:Naphthalenes; D010455:Peptides; D014443:Tyrosine; D005340:Fibrinogen; D000077466:Tirofiban; D000077542:Eptifibatide; D000077284:Abciximab