Patented molecules that counteract the effect of the most common anticoagulant drug

Researchers at IQAC-CSIC have successfully tested molecules that reverse the effect of the anticoagulant heparin, used to treat patients at risk of thrombosis. These new molecules have been patented. Patients treated with heparin may need to block its effect during surgery. The only drug available nowadays has a high molecular weight and may have associated side effects.

Blood sample with the anticoagulant heparin (it can be seen how the blood cells appear to be 'loose' from each other).  Electron microscopy image from IQAC-CSIC.The most common anticoagulant drug is heparin, which is very useful in the routine treatment of patients at risk of thrombosis. However, sometimes it is necessary to block the action of heparin when these patients have to undergo surgery, in order to avoid excessive bleeding. "This is especially critical in patients who need urgent surgery because of an accident. In these cases, the inhibition of circulating heparin in the blood is essential to avoid complications," says Ignacio Alfonso, researcher at IQAC-CSIC.

Other situations where blocking heparin is required include allergic reactions or overdose, which can lead to significant bruising or even uncontrolled bleeding.

Heparin is mainly used as an anticoagulant, but also as an antiviral and anticancer agent. Additionally, its use has increased with the Covid pandemic, to prevent thrombus in coronavirus patients and pregnant women. "Although it is one of the most common anticoagulant drugs, it is not free of danger, therefore it is essential to have more diverse and efficient antidotes," says Ignacio Alfonso.

Currently, the only drug to neutralise the action of heparin is protamine sulphate. However, this is a high molecular weight drug, so it can have adverse effects. Until now, it does not exist on the market any small molecule to inhibit the anticoagulant effect of heparin.

The team led by Alfonso identified some time ago several small molecules that inhibit the effect of heparin. The team has tested now some of these molecules in a murine model and has patented them. This is a first step to design possible drugs.

A blood sample with heparine to which one of the new molecules that counteract the effect of the anticoagulant has been applied (the cells look like 'stuck' to each other).  Electron microscopy image from IQAC-CSIC

The patented molecules are simple which implies a lower risk of complications. The latest trials, published in The Journal of Medicinal Chemistry (ACS), show that these optimised molecules are potent antidotes to heparin.

Nevertheless, the molecules have been tested only in murine model, explains Ignacio Alfonso, so potential drugs are still a long way off. "It is necessary to carry out pharmacokinetic, toxicity and organ accumulation assays. Also, subsequent pre-clinical and clinical trials are required," he adds.

From a chemical point of view, he adds, "the molecules are simple and can be obtained in one or two steps from commercial and relatively cheap compounds," he concludes. The team is now seeking industrial partners interested in further developing these molecules in order to bring them to the market.

The combinatorial chemistry approach

This research has used a methodology based on dynamic combinatorial chemistry, which combines in a single process the selection, identification and preparation of molecules, speeding up the development of new functional compounds.

In contrast to conventional chemistry, which is based on trying to obtain and synthetize a single compound, dynamic combinatorial chemistry is aimed to obtain compounds by combining very simple basic elements, as if they were building blocks, to obtain bigger molecules. These blocks are simple molecules, of which the scientists know accurately how they attach each other, and they are selected according to the goal sought.

"The success of this research supports the dynamic combinatorial chemistry. Moreover, an excellent correlation has been found between the results of the screening and the inhibition of heparin with in vitro enzymatic assays" explains the researcher. "This study validates our approach," concludes Alfonso.

Contact:

Isabel Masip
Deputy Vice-Presidency
for Knowledge Transfer - CSIC
Tel: + 34 – 93 442 65 76
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