Title
Allosteric Inhibition of factor xiiia. Non-Saccharide Glycosaminoglycan Mimetics, but not Glycosaminoglycans, Exhibit Promising Inhibition Profile
Funding Source
National Institutes of Health
Grant Number
HL107152, HL090586
Department
College of Pharmacy
Document Type
Article
Publication Date
7-2016
Abstract
Factor XIIIa (FXIIIa) is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa's active site by using sulfated glycosaminoglycans (GAGs) or non-saccharide GAG mimetics (NSGMs) would lead to the discovery of the first allosteric FXIIIa inhibitors. We tested a library of 22 variably sulfated GAGs and NSGMs against human FXIIIa to discover promising hits. Interestingly, although some GAGs bound to FXIIIa better than NSGMs, no GAG displayed any inhibition. An undecasulfated quercetin analog was found to inhibit FXIIIa with reasonable potency (efficacy of 98%). Michaelis-Menten kinetic studies revealed an allosteric mechanism of inhibition. Fluorescence studies confirmed close correspondence between binding affinity and inhibition potency, as expected for an allosteric process. The inhibitor was reversible and at least 9-fold- and 26-fold selective over two GAG-binding proteins factor Xa (efficacy of 71%) and thrombin, respectively, and at least 27-fold selective over a cysteine protease papain. The inhibitor also inhibited the FXIIIa-mediated polymerization of fibrin in vitro. Overall, our work presents the proof-of-principle that FXIIIa can be allosterically modulated by sulfated non-saccharide agents much smaller than GAGs, which should enable the design of selective and safe anticoagulants.
Recommended Citation
Al-Horani, Rami; Karuturi, R.; Lee, M.; Afosah, D. K.; and Desai, U. R., "Allosteric Inhibition of factor xiiia. Non-Saccharide Glycosaminoglycan Mimetics, but not Glycosaminoglycans, Exhibit Promising Inhibition Profile" (2016). Faculty and Staff Publications. 259.
https://digitalcommons.xula.edu/fac_pub/259
Comments
DOI: 10.1371/journal.pone.0160189
PubMed ID: 27467511
Funding text
This work was funded by grants HL107152 and HL090586 from the National Institutes of Health toURD and the 2016 Nancy and Donald Abraham Postdoctoral Award to RAAH.