Primetime has established a collaboration with Dr. Umesh Desai, Director of the Institute of Structural Biology and Drug Discovery at the Virginia Commonwealth University (VCU) to develop an allosteric, potent and selective inhibitor of factor XIa to act as a safe anticoagulant drug.
The project focuses on the development of anticoagulants by inhibition of factor Xia (FXIa) without major bleeding consequences. Thrombotic disorders such as venous thromboembolism and pulmonary embolism are major challenges in effective and safe anticoagulant therapy. Current anticoagulants used for treating these disorders include the unfractionated heparin, low molecular weight heparin, fondaparinux, and warfarin. The primary targets of these agents are two key proteases, thrombin and factor Xa, which belong to the common pathway of the coagulation cascade. The new anticoagulants that are being developed and expected to be successful because of their high efficacy and relatively low cost to benefit ratio. However, the anticoagulants are prone to cause many adverse effects, particularly hemorrhage. With their ubiquitous use, it becomes important for clinicians to have a sound understanding of anticoagulant pharmacology, dosing, and toxicity. The recent animal studies with either the deletion of FXI gene or the inhibition of FXIa have shown promise to identify new anticoagulants with better safety profiles.
Biochemical screening of VCU's proprietary library of sulfated aromatic (heparin-mimetic) compounds, Dr. Desai’s lab has discovered a compound, SPGG, and several of its analogs with excellent potency and selectivity for human FXIa. These compounds also prevented activation of factor IX and prolonged human plasma and whole blood clotting. SPGG allosterically binds to the heparin-binding site of FXIa . Allosteric inhibitors offer higher selectivity over traditional competitive inhibitors. In addition, an appropriately designed allosteric regulator that does not fully nullify the procoagulant signal may maintain a well-tuned balance between procoagulant and anticoagulant signal, resulting in reduced bleeding complications. SPGG and its analogs showed marked anticoagulant activities in FeCl3-induced thrombosis in carotid artery mice model without affecting bleeding time.