Dynamic Combinatorial Optimization of In Vitro and In Vivo Heparin Antidotes

Daniel Carbajo, Yolanda Pérez, Marta Guerra-Rebollo, Eva Prats, Jordi Bujons, Ignacio Alfonso

Producció científica: Article en revista indexadaArticleAvaluat per experts

5 Cites (Scopus)


Heparin-like macromolecules are widely used in clinics as anticoagulant, antiviral, and anticancer drugs. 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. Here, we use a dynamic combinatorial chemistry approach to optimize heparin binders with submicromolar affinity. 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. The enzymatic assays with selected library members confirm the correlation between the dynamic covalent screening and the in vitro heparin inhibition. 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. Overall, these results underscore the power of dynamic combinatorial chemistry targeting complex and elusive biopolymers.

Idioma originalAnglès
Pàgines (de-a)4865-4877
Nombre de pàgines13
RevistaJournal of Medicinal Chemistry
Estat de la publicacióPublicada - 24 de març 2022


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