Dynamic Combinatorial Optimization of In Vitro and In Vivo Heparin Antidotes

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

Research output: Indexed journal article Articlepeer-review

3 Citations (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.

Original languageEnglish
Pages (from-to)4865-4877
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number6
Publication statusPublished - 24 Mar 2022


Dive into the research topics of 'Dynamic Combinatorial Optimization of In Vitro and In Vivo Heparin Antidotes'. Together they form a unique fingerprint.

Cite this