Science & Technology, Australia (Commonwealth Union) – A groundbreaking anticoagulant has been developed by researchers at the University of Sydney and the University of Geneva, offering a unique ability to halt its anticlotting effects swiftly when required. This innovation holds promise for the creation of safer surgical and post-operative medications that significantly reduce the risk of excessive bleeding.
Employing an innovative methodology, the research team uncovered this novel molecule. The anticoagulant merges a short protein molecule (peptide) sourced from the tsetse fly, a blood-feeding insect, with a synthesized peptide. The linkage between the two peptides can be disengaged on demand, furnishing the anticoagulant with its own regulatory switch.
Researchers of the study state that this fresh approach to drug discovery carries considerable implications for surgical procedures and clot prevention. Moreover, its potential extends to diverse fields such as immunotherapy.
The findings were unveiled recently in Nature Biotechnology.
It was pointed out by the researchers that beyond its application in surgery, anticoagulant therapies are vital for managing various conditions, including heart disease, stroke, and venous thrombosis. However, existing treatment options like heparin and warfarin pose significant challenges, such as the necessity for regular blood coagulation monitoring and the risk of severe bleeding with overdosing.
Approximately 15 percent of emergency hospital admissions due to adverse drug reactions stem from complications related to anticoagulant therapies, underscoring the urgent need for the development of safer and more efficacious treatment alternatives.
Professor Rich Payne from the School of Chemistry is an NHMRC Investigator Leadership Fellow and Deputy Director of the ARC Centre of Excellence for Innovations in Peptide and Protein Science (CIPPS) as well as a coauthor for the study.
Professor Payne says “What’s exciting here is that we have applied a completely novel approach to drug discovery. 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.”
Professor Nicolas Winssinger, leading the research at the Department of Organic Chemistry at the University of Geneva, expressed, his views pointing out that this discovery surpasses mere development of a novel anticoagulant and its corresponding antidote. The supramolecular approach they propose exhibits remarkable adaptability, easily extendable to various therapeutic targets, holding significant promise especially in the realm of immunotherapy.
The newfound anticoagulant presents a more dependable and user-friendly alternative for surgical procedures. Heparin, conventionally utilized in surgeries, comprises a blend of polymers extracted from pig intestines, posing risks of severe bleeding and necessitating coagulation tests during surgery. The synthetic anticoagulant devised by the collaborative efforts of Geneva and Sydney teams offers a solution to the purity and availability issues linked with heparin.
A pivotal aspect of this breakthrough involves leveraging a peptide nucleic acid (PNA) to tether two molecules that obstruct thrombin, the enzyme responsible for fibrin production in blood clots. In this innovation, a peptide molecule derived from tsetse flies and a synthetic ketobenzothiazole-containing peptide converge on two distinct sites of thrombin, forming a ‘supramolecule’ connected by a PNA double helix, akin to DNA in structure.
The PNA double helix comprises two strands capable of weak, non-covalent bonding, which can be disassembled as needed. The research demonstrates that by introducing appropriately matched free PNA strands, the two thrombin-binding molecules can be dissociated, rendering the anticoagulant inactive. This breakthrough heralds a significant advancement in the field.
The peptide from the tsetse fly, initially developed at the University of Sydney’s laboratories, underwent rigorous testing for its anticoagulant properties. These evaluations occurred both in vitro, using human and mouse blood samples, and in vivo, with experiments conducted on mice.
Beyond its anticoagulant effects, the supramolecular mechanism underlying this peptide’s action holds promise for broader applications, especially in the realm of immunotherapy, notably in CAR-T therapies.
The researchers further indicated that while CAR-T therapies represent a significant breakthrough in combating specific cancers, their utilization comes with a notable risk of triggering an immune system overreaction, potentially leading to fatal consequences. The capacity to swiftly deactivate the treatment through an easily accessible antidote could mark a pivotal advancement in enhancing the safety and effectiveness of CAR-T therapies.
