A new approach to creating ‘surpamolecules’ for drug discovery has potential applications in immunotherapy, as well as a breakthrough in designing an anticoagulant with on-demand reversibility.
Researchers at the University of Sydney and University of Geneva have developed a novel anticoagulant that can quickly stop its anticlotting action ‘on demand’. This could result in new drugs for surgical and post-operative use that reduce the risk of severe bleeding.
The research team utilized an entirely new method to discover the molecule, which combines a short protein.The bonds that hold together a molecule from a tsetse fly, a blood-feeding insect, and a second synthesized peptide can be broken on demand. This provides the anticoagulant ingredient with its own on-off switch, making it a potential game-changer in surgery and for suppressing blood clots. This approach could also be used in other fields such as immunotherapy. The findings are published in Nature Biotechnology. Anticoagulant therapies are crucial for managing various conditions, including heart disease, stroke, and more.Venous thrombosis is a serious condition that requires treatment, but the current options like heparin and warfarin have some issues. These include the need for regular monitoring of blood coagulation and the risk of serious bleeding if too much is taken. About 15% of emergency hospital admissions due to adverse drug reactions are because of problems with anticoagulant treatments, so it’s important to find new, safer, and more effective options. Professor Rich Payne from the School of Chemistry is working on this as an NHMRC Investigator Leadership Fellow and Deputy Director of the ARC Centre of Excellence for Innovations in Peptide.The author of the research is a member of the Centre for Innovation in Point-of-Care Testing for Patient Self-Testing and Protein Science (CIPPS). He stated that the exciting aspect of the research is the innovative approach to drug discovery. The anticoagulant developed utilizes a concept called supramolecular chemistry, which allows the two necessary active molecules to self-assemble for coagulation suppression. The structure also enables the application of an antidote that can rapidly disassemble the combined molecules, leading to a quick cessation of the active combination and the anticoagulant effect – an unprecedented feat in drug discovery.According to Professor Nicolas Winssinger of the Department of Organic Chemistry at the University of Geneva, the significance of this discovery extends beyond the creation of a new anticoagulant and its corresponding antidote. The supramolecular approach presented is highly adaptable and has the potential to be applied to various other therapeutic targets, making it particularly promising in the area of immunotherapy.
Furthermore, the new anticoagulant has the potential to revolutionize surgical procedures by providing a more dependable and user-friendly alternative to the commonly used heparin, which is derived from a combination of polymers of varying lengths extracted from pig intestine.The use of heparin in medical settings poses a challenge due to the potential for serious bleeding as a side effect and the need for coagulation tests during surgery. A new synthetic anticoagulant created by a team in Geneva and Sydney may offer a solution to the issues of purity and availability associated with heparin.
This breakthrough involves the use of a peptide nucleic acid (PNA) to connect the two molecules that bind and inhibit the action of thrombin, the enzyme responsible for the formation of fibrin, the substance that forms blood clots.
In this instance, the peptide molecule derived from the tsetse fly and a synthetic ketobenzothiazole are used.
Thrombin-binding peptide forms a ‘supramolecule’ with two distinct sites on thrombin, connected by a PNA double helical linker that resembles DNA.
The two strands of PNA in the double helix can join together through weak non-covalent bonds that can be separated when necessary. The research team demonstrated that introducing appropriately matched strands of free PNA can separate the two thrombin-binding molecules. As a result, the two free PNA strands are no longer effective as anticoagulants, marking a significant advancement in the field.
The tsetse fly peptide was created in University of Sydney laboratories.
Tests were conducted at Sydney on human and mouse blood samples, as well as in mice in vivo, to evaluate the effectiveness of the supramolecular anticoagulant.
This concept of activating and deactivating the active principle could be valuable in the field of immunotherapy, especially for CAR-T therapies, in addition to addressing anticoagulation issues.
CAR-T therapies have advanced cancer treatment, but they carry a risk of immune system storm, which can be deadly. The ability to regulate the active principle could be beneficial in mitigating this risk.Developing a rapid-acting antidote to improve the safety and effectiveness of CART-T therapies is a critical advancement.
