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Other representative Hep-binding molecular scaffolds are self-assembled cationic amphiphiles (17) or peptide dendrimers. Recent reports on alternative macromolecules to reverse heparin drugs include a polymeric polycationic dendrimer (UHRA), (12) a monoclonal antibody (idarucizumab), (13) a modified version of the recombinant human coagulation factor Xa (andexanet alpha), (14) as well as peptides (15) and peptidomimetics (16) mimicking protamine. (8−10) However, the number of antidotes for heparin-type drugs is quite limited: the one mostly used is protamine, (11) a small arginine-rich nuclear protein. For a safer usage of Hep, the accessibility to a family of efficient reversal agents is desirable, especially for cases of overdose, life-threatening bleeding, or urgent high-risk surgery. Heparin (Hep, Figure 1a) is a highly anionic glycosaminoglycan (GAG) (1) extensively used in clinics, mainly as an anticoagulant (2,3) and also as an antiviral (4,5) and anticancer (6,7) agent. Overall, these results underscore the power of dynamic combinatorial chemistry targeting complex and elusive biopolymers. Moreover, both ex vivo and in vivo blood coagulation assays with mice show that the optimized molecules are potent antidotes with potential use as heparin reversal drugs. The enzymatic assays with selected library members confirm the correlation between the dynamic covalent screening and the in vitro heparin inhibition.
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The recognition of heparin by the most amplified members of the dynamic library has been studied with different experimental (SPR, fluorescence, NMR) and theoretical approaches, rendering a detailed interaction model. Here, we use a dynamic combinatorial chemistry approach to optimize heparin binders with submicromolar affinity. However, the search of heparin antidotes based on small synthetic molecules to control blood coagulation still remains a challenging task due to the physicochemical properties of this anionic polysaccharide. Heparin-like macromolecules are widely used in clinics as anticoagulant, antiviral, and anticancer drugs.