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

Research output: Contribution to journalArticle

Authors

  • Daniel K. Afosah
  • Stephen Verespy
  • Rami A. Al-Horani
  • Rio S. Boothello
  • Rajesh Karuturi
  • Umesh R. Desai

External Institution(s)

  • Virginia Commonwealth University

Details

Original languageEnglish (US)
Pages (from-to)1101-1105
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number6
StatusPublished - Apr 1 2018
Peer-reviewedYes

Abstract

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 (ΔY = 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 anticoagulants today.

    Research areas

  • Allosteric inhibition, Anticoagulants, Enzyme regulation, Heparin-binding site, Thrombin

Citation formats

APA

Afosah, D. K., Verespy, S., Al-Horani, R. A., Boothello, R. S., Karuturi, R., & Desai, U. R. (2018). A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin. Bioorganic and Medicinal Chemistry Letters, 28(6), 1101-1105. https://doi.org/10.1016/j.bmcl.2018.01.069

Harvard

Afosah, DK, Verespy, S, Al-Horani, RA, Boothello, RS, Karuturi, R & Desai, UR 2018, 'A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 6, pp. 1101-1105. https://doi.org/10.1016/j.bmcl.2018.01.069