A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Afosah, Daniel K.^1,2  Verespy, Stephen, III^2,3  Al-Horani, Rami A.^2,4  Boothello, Rio S.²  Karuturi, Rajesh²  Desai, Umesh R.^1,2 

[1] Virginia Commonwealth Univ, Dept Med Chem, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Inst Struct Biol Drug Discovery & Dev, Richmond, VA USA

[3] Virginia Commonwealth Univ, Dept Chem, Box 2006, Richmond, VA 23284 USA

[4] Xavier Univ, Div Basic Pharmaceut Sci, New Orleans, LA 70125 USA

关键词: Allosteric inhibition;    Anticoagulants;    Thrombin;    Heparin-binding site;    Enzyme regulation;   

DOI  :  10.1016/j.bmcl.2018.01.069

来源: Elsevier

【 摘 要 】

Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce sub-maximal inhibition of coagulation proteases, thereby avoiding/reducing bleeding risk. We present the design of a group of sulfated benzofuran dimers that display heparin-binding site-dependent partial allosteric inhibition of thrombin against fibrinogen (Delta Y = 55-75%), the first time that a small molecule (MW < 800) has been found to thwart macromolecular cleavage by a monomeric protease in a controlled manner. The work leads to the promising concept that it should be possible to develop allosteric inhibitors that reduce clotting, but do not completely eliminate it, thereby avoiding major bleeding complications that beset anti-coagulants today. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

Free