Researchers at the University of Sydney and University of Geneva have developed a new anticoagulant, where the anticlotting action can be rapidly stopped ‘on demand’. This could lead to new surgical and post-operative drugs that minimise the risk of serious bleeding.
The anticoagulant combines a short protein molecule (a peptide) from a tsetse fly – a blood-feeding insect – with a second, synthesised peptide. The bonds holding the two peptides together can be broken on demand, providing the anticoagulant ingredient with its own on-off switch.
The potential applications are in surgery, with suppressing blood clots, and in other fields such as immunotherapy. The suppression of blood clots could assist in managing heart disease, stroke and venous thrombosis.
Advantages
Current treatment options, including heparin (extracts from the intestine of pigs) and warfarin, have drawbacks, including the need for regular monitoring of blood coagulation and the risk of serious bleeding in the event of overdose.
Whereas the new anticoagulant could offer a more reliable and easier-to-use option for surgical procedures. Furthermore it addresses problems of purity and availability, both of which are associated with heparin.
Scientific basis
The new compound is based on a peptide nucleic acid (PNA) that can link the two molecules that bind and block the action of thrombin, the enzyme that produces fibrin that makes up our blood clots.
The tsetse-fly-derived peptide molecule and a synthetic ketobenzothiazole containing peptide bind to two distinct sites on thrombin as a ‘supramolecule’ connected by a PNA double helical linker, similar in shape to DNA.
These two strands of PNA that make up the double helix can come together via relatively weak – non-covalent – bonds that can be broken when needed. The research team has shown that by introducing correctly matched strands of free PNA, it is possible to dissociate the two thrombin-binding molecules. The two free PNA strands are no longer active as anticoagulants. This is a major innovation in the field.
Lead researcher Professor Rich Payne says of the research: “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.”
Payne adds: “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.”
Research paper
The research has been published in the journal Nature Biotechnology, titled “Development of supramolecular anticoagulants with on-demand reversibility.”
