Obtained a synthetic single molecule which inhibits the anticoagulant heparin

Scientists at the IQAC-CSIC have obtained a synthetic single molecule which inhibits heparin, the most used anticoagulant drug nowadays. The development has been possible by dynamic combinatorial chemistry. Dynamic chemistry makes possible quickly discovering active molecules and drugs.

 Microscopy image of a thrombo (IQAC-CSIC)“Patients who are at risk of suffering thrombosis are usually treated with heparin. Nevertheless, sometimes these patients can suffer allergic reactions to heparin or overdoses, which can cause haematomes and uncontrolled haemorrhages”, explains Ignacio Alfonso, a scientist at the Instituto de Química Avanzada de Cataluña (IQAC-CSIC), in Barcelona.

 

This is a critical situation when patients treated with heparin have to be urgently and unexpectedly submitted to surgical treatment. Then, it is essential to inhibit heparin effects in the blood circulation to avoid complications derived from excessive bleeding.

“We have used dynamic combinatorial chemistry to find a new single molecule which can act as antagonist of a complex biomedical like the heparin, says Alfonso. The results of this research have been recently published and highlighted as a ‘hot paper’ in the Angewandte Chemie International Edition journal.

A small molecule

This is not the first antagonist molecule of heparin, but one of the smallest, which is an advantage. Most heparin antagonists used nowadays are macromolecules. “This is due to the structural and functional complexity of heparin, and makes very difficult to design inhibitors”, points out Alfonso.

Heparin is one of the most commonly used drugs, but the design of small molecules to modulate its effects is hard  because its structural complexity.
The scientists tested the new molecule in an ‘in vitro’ assay and have confirmed that it reactivates the coagulation factor FXa, which is inhibited by heparin, as Alfonso explains.

Dynamic chemistry

“In our research we have used a covalent dynamic selection to identify new ligand molecules for heparin, assembled from extremely simple pieces”. The new ligand binds to heparin and ‘blocks’ its action. 

Dynamic chemistry makes possible quickly discovering active molecules and drugs. Compared to more conventional chemistry, based often on searching and isolating a compound, in the dynamic chemistry new substances are obtained by the strategy of combining very simple pieces joined by dynamic bonds. These pieces, which are selected according to the expected results, bind and interact differently depending on the stimulus they receive.  

This technology has a great potential for developing new active molecules and diagnostic methods based on the interaction of selected molecules. The same scientific team recently obtained a new method for the precise and early diagnosis of cystinuria disease, through urine testing.

Miriam Corredor, Daniel Carbajo, Cecilia Domingo, Yolanda Pérez, Jordi Bujons, Angel Messeguer, Ignacio Alfonso. Dynamic covalent identification of an efficient heparin ligand. Angewandte Chemie International Edition. DOI: 10.1002/anie.201806770