AsianScientist (Nov. 17, 2015) – Scientists from China have resolved the crystal structure between a clinically approved blood clot dissolving drug and one of its binding partners. Their work, published in the Journal of Biological Chemistry, paves the way for the design of next-generation thrombolytic drugs with improved efficacy and reduced side effects.
Blood flows continuously throughout body, but quickly stops to prevent excessive blood loss when one gets a cut or injury. Blood clots are healthy and lifesaving when they stop unwanted bleeding, but they can also happen in pathological conditions. Abnormal blood clots—or thrombosis—can cause stroke, heart attack or other serious medical problems. Thrombosis is estimated to be the cause of one in four deaths worldwide.
To date, the most effective blood clot lysis therapy (thrombolytic therapy) is to boost an internal blood clot lysis enzyme, tissue-type plasminogen activator (tPA) by infusing recombinant tPA (rtPA) into blood. This therapy is FDA-approved and rtPA is the most effective thrombolytic drug for ischemic strokes, myocardial infarction and pulmonary embolism.
High doses of recombinant tPA (up to 100 mg per 50 kg) are typically needed in clinical applications, in part due to the rapid inactivation of recombinant tPA by endogenous physiological inhibitors (plasminogen activators inhibitor 1, PAI-1). However, high doses of tPA can lead to dangerous or even fatal side effects, such as intra-cranial hemorrhage and neurotoxicity. Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort.
A team of scientists led by Professor Huang Mingdong from Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, determined the crystal structure of rtPA in complex with its endogenous inhibitor (PAI-1) at 3.16 Å. This structure presents precise details, with atomic resolution, on how the tPA is inhibited by PAI-1.
In this structure, the RCL of PAI-1 serves as a bait to attract the rtPA onto the top of PAI-1 molecule, forming a large interface of 1,202 Å2. Protein engineering of tPA by mutations based on this structure can maximize rtPA resistance to inhibition by PAI-1, hence prolonging the half life of rtPA in vivo. This long-sought structure also explains the PAI-1-resisting property of third generation rtPAs such as Tenecteplase.
This work could inform the development of next generation of blood clot lysis agents with higher potency by increasing its half life in blood. In addition, by reducing drug dose needed in the therapy, and it reduces the unwanted side effects.
The article can be found at: Gong et al. (2015) Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1.
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Source: Chinese Academy of Sciences.
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