New anti-clotting agent has its own 'off switch'

Friday, 10 May, 2024

New anti-clotting agent has its own 'off switch'

Researchers from the University of Geneva (UNIGE) and The University of Sydney (USyd) have developed an anticoagulant whose anti-clotting action can be rapidly stopped on demand, which could enable new surgical and post-operative drugs that minimise the risk of serious bleeding. Their work has been published in the journal Nature Biotechnology.

In addition to surgical applications, anticoagulant therapies are essential for managing a wide range of conditions, such as heart disease, stroke and venous thrombosis. However, current treatment options have major drawbacks, including the need for regular monitoring of blood coagulation and the risk of serious bleeding in the event of overdose or trauma. About 15% of emergency hospital admissions due to adverse drug reactions are attributable to complications from anticoagulant treatments, emphasising the need for safer and more effective therapeutic options.

A group led by UNIGE’s Professor Nicolas Winssinger, in collaboration with USyd’s Professor Richard Payne, has now created an anticoagulant active ingredient with an ‘antidote’ to reverse its effect rapidly and specifically. The anticoagulant consists of a peptide from a blood-feeding tsetse fly, plus a second, synthesised peptide containing ketobenzothiazole, linked together by a peptide nucleic acid (PNA) double helical linker that is similar in shape to DNA. Together, the two molecules target distinct sites of thrombin — a protein whose action is central for blood coagulation — as one ‘supramolecule’.

Having bound to the thrombin, the molecules combine to inhibit its activity, thereby reducing its coagulant effect. Meanwhile, the connecting strands of PNA feature relatively weak bonds that can be broken on demand. The researchers showed that by introducing correctly matched strands of free PNA, it is possible to dissociate the two thrombin-binding molecules, thus neutralising the anticoagulant.

“What’s exciting here is that we have applied a completely novel approach to drug discovery,” Payne said.

“The anticoagulant we have developed uses what we call supramolecular chemistry. This allows the two active molecules needed to suppress coagulation to self-assemble.

“The architecture also means we can apply an antidote that can quickly disassemble the joined molecules, triggering a rapid cessation of the active combination and the anticoagulant effect. This has never been done before in drug discovery.”

The new anticoagulant could offer a more reliable and easier-to-use option for surgical procedures. The current use of heparin — a mixture of polymers of different lengths extracted from pig intestine — in the clinic is problematic due to the risk of serious bleeding side effects and requires coagulation tests during surgery. The synthetic anticoagulant could help solve the problems of purity and availability associated with heparin.

Beyond the problem of anticoagulation, the supramolecular concept of activating and deactivating the active principle could be of interest to the field of immunotherapy, particularly for CAR-T therapies. Although CAR-T therapies are one of the major advances in the treatment of certain cancers in recent years, their use is associated with a significant risk immune system overreaction (cytokine storm), which can be fatal. The ability to rapidly deactivate treatment with an accessible antidote could therefore improve the safety and efficacy of CART-T therapies.

“The supramolecular approach proposed is remarkably flexible and can be easily adapted to other therapeutic targets,” Winssinger said. “It is particularly promising in the field of immunotherapy.”

Image illustrates the combined action of two molecules cooperating to inhibit thrombin. The antidote dissociates the two molecules, preventing the cooperativity. The association and dissociation of the two molecules is controlled by hybridisation of oligonucleotides. Image ©Millicent Dockerill/Nicolas Winssinger.

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