A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding

Abstract

Background Human factor XIa (FXIa) is an actively pursued target for development of safer anticoagulants. Our long‐standing hypothesis has been that allosterism originating from heparin‐binding site(s) on coagulation enzymes is a promising approach to yield safer agents. Objectives To develop a synthetic heparin mimetic as an inhibitor of FXIa so as to reduce clot formation in vivo but not carry high bleeding risk. Methods We employed a gamut of methods involving synthetic chemistry, biophysical biochemistry, enzyme assays, blood and plasma coagulation assays, and in vivo thrombosis models in this work. Results Sulfated chiro‐inositol (SCI), a non‐saccharide mimetic of heparin, was synthesized in three steps in overall yields of >50%. SCI inhibited FXIa with potency of 280 nmol/L and preferentially engaged FXIa's heparin‐binding site to conformationally alter its active site. SCI inhibition of FXIa could be rapidly reversed by common antidotes, such as protamine. SCI preferentially prolonged plasma clotting initiated with recalcification, rather than thromboplastin, alluding to its intrinsic pathway‐based mechanism. Human blood thromboelastography indicated good ex vivo anticoagulation properties of SCI. Rat tail bleeding and maximum‐dose‐tolerated studies indicated that no major bleeding or toxicity concerns for SCI suggesting a potentially safer anticoagulation outcome. FeCl3‐induced arterial and thromboplastin‐induced venous thrombosis model studies in the rat showed reduced thrombus formation by SCI at 250 μg/animal, which matched enoxaparin at 2500 μg/animal. Conclusions Overall, SCI is a highly promising, allosteric inhibitor of FXIa that induces potent anticoagulation in vivo. Further studies are necessary to assess SCI in animal models mimicking human clinical indications.

Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

“…For some time now, we have been pursuing non-polymeric, non-saccharide mimetics of heparin/heparan sulfate as anti-viral [50][51][52][53][54], anti-cancer [55,56], and anti-thrombotic agents [57,58]. The advantage with these mimetics is that these are fully synthetic, easily characterizable, and highly amenable to advanced rational drug design possibilities.…”

“…The unique aspect of SPGG is its globular structure that theoretically can interact with diverse HS-binding proteins. In fact, our earlier work on SPGG has shown that it interacts with coagulation factor XIa [57,61] and glycoprotein gD [50], two completely different HS-binding proteins. Thus, we reasoned that the probability of targeting multiple proteins involved in cellular entry of HCMV, e.g., glycoprotein gB, PDGF-R, EGF-R, and neuropilin, would be higher with SPGG than with other non-saccharide mimetics developed so far.…”

Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

“…The synthetic scheme of the NSGMs was previously reported [ 30 , 31 , 38 , 39 , 40 , 41 ]. All the molecules were characterized by NMR and ultra-performance liquid chromatography (UPLC) − electrospray ionization mass spectrometry (ESI-MS).…”

“…These molecules, referred to as non-saccharide GAG mimetics (NSGMs), have now been shown to bind and functionally modulate multiple GAG-binding proteins [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. For example, distinct NSGMs have been identified as ligands of fibroblast growth factor receptor-1 [ 28 ], antithrombin [ 33 , 34 ], neutrophil elastase [ 29 ], coagulation factor Xia [ 30 , 35 ], plasmin [ 31 ], and viral glycoprotein D [ 32 ], each of which are known to bind to heparin. In fact, several NSGMs have been found to display one-to-one correspondence with specific GAG sequences [ 28 , 36 ].…”

“…Using this concept, distinct NSGMs have been developed as promising anticoagulants [ 35 ], antifibrinolytics [ 31 ], anticancer [ 39 ], anti-inflammatory [ 29 ], and antiviral agents [ 32 ]. More importantly, our work has shown that initial “hits” can be systematically developed through an appropriate hit-to-lead optimization strategy into potent and selective candidates, with favorable pharmacokinetic properties and minimum adverse side-effects [ 30 , 36 , 40 , 42 ].…”