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Louisiana Biomedical Research Network

Rami Al-Horani

Link to Pubmed Publications

Xavier University


Project Title

Inhibition of Factor XIIIa by Sulfonated Glycosaminoglycan Mimetics as Potential Avenue to Novel Anticoagulants


Mentor

Rinku Majumder, LSUHSC-NO


Funding Periods

Pilot Project (May 1, 2019 - April 30, 2020)

Startup Project (May 1, 2018 - April 30, 2019)

Abstract


Venous thromboembolism (VTE) remains a major public health crisis. VTE is the third most common cardiovascular disease and annually affects about 1 million people in the US. VTE is responsible for more than 100,000 annual deaths in the US. Furthermore, a 2-way link between VTE and cancer has also been confirmed. Patients with cancer have at least 4-fold increased risk for VTE in comparison with patients without cancer. Nevertheless, clinically used anticoagulants are plagued with a number of drawbacks including the life-threatening risk of internal bleeding. New approaches to safely prevent and/or treat VTE are highly clinically significant. Factor XIIIa (FXIIIa) is a transglutaminase procoagulant that is different from all other physiologic procoagulants which are serine proteases. This unique biochemical aspect of FXIIIa has been under investigation in the context of VTE mechanism. Venous thrombi from FXIII-deficient mice were found to be significantly smaller in size. Various studies also suggested that specific FXIIIa polymorphism provides a moderate protection against VTE and that heterozygous FXIII-deficient mice do not show signs of excessive bleeding. Therefore, FXIIIa may serve as a potential therapeutic target to develop a new effective treatment for VTE that does not significantly increase the bleeding risk. In vitro experiments show that treating normal human blood with a transglutaminase active site inhibitor dose-dependently increases RBC extrusion from contracting clots and reduces clot size. Yet, it remains unclear whether FXIIIa inhibition is a viable approach for anticoagulation in vivo. At present, these studies are hindered, in part, by the lack of specific FXIIIa inhibitors. In fact, very few FXIIIa inhibitors have been reported thus far, most of which are not selective as they target the thiol-containing active site. Thus, I have proposed sulfonated glycosaminoglycan (GAG) mimetics as a platform to discover and subsequently rationally design FXIIIa inhibitors. These GAG mimetics are projected to potently and selectively inhibit FXIIIa through allosteric modulation, a mechanism often exploited by nature to achieve specific regulation. In preliminary studies, I discovered two sulfonated GAG mimetics that inhibit FXIIIa with micromolar potencies. Not only that, but these two molecules also inhibited FXIIIa-mediated polymerization of fibrin(ogen) which is one of the physiologic functions of human FXIIIa. Molecular modeling studies projected a plausible binding site for these molecules on FXIIIa. Therefore, in this proposal, I specifically aim to use a multidisciplinary approach to further establish the principles of effective and selective inhibition of FXIIIa by sulfonated GAG mimetics. I will synthesize an advanced library of sulfonated GAG mimetics and evaluate their biochemical, biophysical, and biological aspects to determine their anticoagulant potentials. The long-term goal of research in this area is to develop potent and specific inhibitors of FXIIIa so as to 1) enhance our understanding of FXIIIa contribution to the whole coagulation physiology and pathology and 2) investigate an alternative approach to modulate FXIIIa through allostery so as to pave the way to a novel and transforming potent and safe anticoagulant therapy to prevent and/or treat thrombotic disorders.