Tapping nature’s medicine cabinet to develop anticoagulant drug

25 Feb 2016 NUS scientists are studying how to stop blood from clotting while not causing uncontrollable bleeding at similar doses.

Thrombosis is one the main causes of morbidity and mortality worldwide. In Singapore, cardiovascular thrombosis alone caused 27.1% of deaths in 2010 (1). Many of the current treatment options, namely drugs to prevent clotting, are inadequate, due to side effects such as bleeding, narrow therapeutic windows and unpredictable anticoagulation efficacy. Therefore, new and better therapeutics are needed.

A team led by Prof Patricia NUTTALL from the University of Oxford, Dr Maria KAZIMIROVA from Slovak Academy of Sciences and Prof Kini R MANJUNATHA from the Department of Biological Sciences (DBS) in NUS studied variegin, a novel inhibitor of blood coagulation factor thrombin that was isolated from the salivary gland extract of the tropical bont tick, Amblyomma variegatum (2). One of the researchers’ main observations is that variegin appears to be very effective in stopping blood from clotting while not causing uncontrollable bleeding at similar doses. Together with Prof Mark CHAN from the Cardiovascular Research Institute at the Yong Loo Lin School of Medicine, the group has now shifted to translating variegin into human application, which was awarded an National Medical Research Council grant to develop variegin as an anticoagulant to be used during arterial thrombosis events.

So far, pre-clinical data for variegin in rat thrombosis and bleeding models showed very promising data. Variegin appears to have a much larger therapeutic window compared to unfractionated heparin, the standard drug used in clinics. This means that for variegin, effective anticoagulation can be achieved with a significantly lower risk of undesirable bleeding, making it a much safer option for heart vessel stenting and heart bypass surgery. The group hopes to tie up the pre-clinical pharmacokinetics and pharmacodynamics studies as soon as possible to move into first-in-human trials. The NUS Drug Development Unit is conducting further tests on variegin to meet the pharmaceutical industry’s stringent standards for novel human drugs.

Possibly the biggest achievement thus far has been the group’s success in attracting Dr KOH Cho Yeow back to DBS. Dr Koh, who was a Ph.D. student in Prof Manjunatha’s laboratory and contributed immensely to the discovery of variegin, left for Seattle shortly after graduating but has since returned to DBS after five years to pursue clinical development of variegin. On what drew him back to Singapore, he said, “The strong collaboration between diverse teams that included protein chemists, biologists and clinicians was a major attraction.”

In addition to drug development, the group is also exploring other ways to utilise the anticoagulant. Dr Koh recently won a Singapore-MIT Alliance for Research and Technology Innovation Grant for the development of a blood stabilising agent to be used in blood collection devices. Initial data showed extensive stabilisation of blood stored in some of the new anticoagulants developed in the laboratory. A prototype of the blood collection device will be constructed this year.

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A fully engorged female Amblyomma variegatum. [Image credit: Dr Maria Kazimirova, Slovakia]

 

References

1. Chan MY. "Thought Leadership on Thrombotic Disorders in South East Asia." ASEAN Heart J 22 (2014) 4.

2. Koh CY, Kazimirova M, Trimnell A, Takac P, Labuda M, Nuttall PA, Kini RM. "Variegin, a novel fast and tight binding thrombin inhibitor from the tropical bont tick." The Journal of biological chemistry 282 (2007) 29101.