Synthetic Anti-Clotting Agent Derived from Bloodsucking Organisms Saliva

Ticks, mosquitoes, and leeches are naturally equipped with a rapid method to prevent blood clotting while they feed on their hosts.

A group of researchers from Duke University has uncovered the secret behind this mechanism, which could be used as an anti-clotting drug, potentially replacing heparin during angioplasty, dialysis, surgeries, and other medical treatments.

The researchers report a synthetic chemical that replicates the properties of substances found in bloodsucking animals' saliva. The research was published in  Nature Communications. Crucially, the novel molecule may also be quickly reversed, allowing coagulation to restart as necessary following therapy.

Biology and evolution figured out anti-coagulation multiple times with a highly potent strategy, it is the perfect model.”

Bruce Sullenger Ph.D., Professor and Study Senior Author, Department of Surgery, School of Medicine, Duke University

Bruce Sullenger is also associated with the Departments of Cell Biology, Neurosurgery, and Pharmacology & Cancer Biology.

Sullenger and collaborators at Duke University and the University of Pennsylvania, with lead author Haixiang Yu, Ph.D., who is part of Sullenger’s lab, began their investigation based on the observation that all blood-sucking organisms have evolved a comparable mechanism to impede blood clotting.

Their saliva contains an anti-clotting chemical that works in two ways: First, it attaches itself to the host's blood's clotting proteins' surface, then it penetrates the protein's core to momentarily stop clotting during a blood meal.

To achieve the dual-action anti-clotting function against thrombin and factor Xa in human blood, the research team focused on engineering molecules to target specific proteins within the sequence of over two dozen molecules involved in clotting. Blood-sucking organisms target different proteins among these molecules.

The next task was to figure out how to turn the process around, which was necessary for clinical applications to prevent bleeding in patients. The activation process was completely understood, allowing the researchers to reverse engineer an antidote that rapidly reinstates clotting.

Yu said, “We believe this approach could be safer for patients and generate less inflammation, as well.”

Its synthetic nature sets it apart from heparin, which has been the clinical standard for the past 100 years. Since heparin cannot be obtained from pig intestines, extensive agricultural infrastructure that produces pollutants and greenhouse gases is necessary.

This is part of a new passion of mine – improving agents that control blood clotting to help patients, while also being responsible from a climate perspective, the medical field is starting to recognize that there is a big problem here, and we need to find alternatives to using animals for making medicines.”

Bruce Sullenger Ph.D., Professor and Study Senior Author, Department of Surgery, School of Medicine, Duke University

Source:
Journal reference:

‌Yu, H., et al. (2024) Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors. Nature Communications. doi.org/10.1038/s41467-024-48211-6

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