Tsetse fly protein provides an anticoagulant with its own on-off switch

The research team applied a completely new method to discover this molecule. Anticoagulants combine short protein molecules (peptides) from the blood-sucking insect tsetse fly with a second synthetic peptide. The bond connecting the two peptides can be broken if necessary, providing the anticoagulant component with its own on/off switch.

This new drug discovery approach has the potential to revolutionize surgical procedures and blood clot control. It may also be applicable to other fields such as immunotherapy.

The result is today. nature biotechnology.

In addition to surgical applications, anticoagulant therapy is essential in the management of a wide range of diseases such as heart disease, stroke, and venous thrombosis. However, current treatment options such as heparin and warfarin have major drawbacks, including the need for regular monitoring of blood clotting and the risk of serious bleeding in case of overdose.

Approximately 15% of emergency hospitalizations due to side effects are due to complications from anticoagulant therapy, highlighting the importance of developing new safer and more effective treatment options.

Professor Rich Payne from the Department of Chemistry is an NHMRC Investigator Leadership Fellow, deputy director of the ARC Center of Excellence for Innovations in Peptide and Protein Science (CIPPS), and co-author of the study.

“What's interesting here is that we've applied a completely new approach to drug discovery. The anticoagulant we've developed uses what's called supramolecular chemistry. “It allows two active molecules to self-assemble.”

“This structure also means that we can apply an antidote that can rapidly break down bound molecules and quickly stop active binding and anticoagulation.

“This has never been done before in drug discovery.”

Lead researcher Professor Nicholas Winsinger from the Department of Organic Chemistry at the University of Geneva said: “These results go beyond the development of new anticoagulants and related antidotes. The proposed supramolecular approach is surprising. “It is very flexible and can be easily adapted to other applications.” It is particularly promising in the field of immunotherapy. ”

revolution in surgery

New anticoagulants may offer more reliable and easier-to-use options in surgery. Heparin, commonly used in this field, is a mixture of polymers of various lengths extracted from pig intestines. The use of heparin in the clinic is problematic due to the risk of serious bleeding side effects, and coagulation testing is required during surgery. A new synthetic anticoagulant developed by a team in Geneva and Sydney could help solve the purity and availability problems associated with heparin.

One of the breakthroughs in this research lies in the use of peptide nucleic acids (PNAs), which combine two molecules that bind to and block the action of thrombin, the enzyme that produces the fibrin that makes up blood clots.

In this case, a tsetse fly-derived peptide molecule and a synthetic ketobenzothiazole-containing peptide bind to two different sites on thrombin as a “supramolecular” connected by a PNA duplex linker similar in shape to DNA.

These two PNA strands that make up the double helix can be linked through relatively weak (noncovalent) bonds that can be broken if necessary. The research team showed that by introducing correctly matched free PNA strands, it was possible to dissociate two thrombin-binding molecules. The two free PNA chains lose their anticoagulant activity. This is a major innovation in this field.

The tsetse fly peptide was developed in a laboratory at the University of Sydney. Testing the efficacy of supramolecular anticoagulants was also tested on human and mouse blood samples in Sydney. alive with a mouse.

Useful for immunotherapy

Beyond the anticoagulation issue, this supramolecular concept of activation and inactivation of active ingredients could be of great interest in the field of immunotherapy, especially CAR-T therapy.

CAR-T therapy is one of the major advances in the treatment of certain cancers in recent years, but its use carries a significant risk of immune system storming, which can be fatal. The ability to rapidly inactivate treatments with available antidotes could be an important advance in improving the safety and efficacy of CART-T treatments.