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Molecules 2015, 20(1), 608-624;

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editor: Vito Ferro
Received: 30 October 2014 / Accepted: 26 December 2014 / Published: 5 January 2015
(This article belongs to the Special Issue Glycosaminoglycans and Their Mimetics)
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Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%–100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design. View Full-Text
Keywords: allosteric inhibitors; library screening; plasmin; sulfated glycosaminoglycan mimetics allosteric inhibitors; library screening; plasmin; sulfated glycosaminoglycan mimetics

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Al-Horani, R.A.; Karuturi, R.; White, D.T.; Desai, U.R. Plasmin Regulation through Allosteric, Sulfated, Small Molecules. Molecules 2015, 20, 608-624.

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