Structural Biology
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 Targeting the X-factor to tackle cardiovascular disease

Coagulation Factor XI and the contact system:

It is well understood that circulating plasma proteins and platelets play a pivotal role in blood clotting and cardiovascular disease. Factor XI has a unique structure among the coagulation factors as it circulates as a disulphide linked dimer. We have previously determined the full length factor XI zymogen crystal structure suggesting a novel transactivation mechanism for a serine proteinase (1). Analysis of the structure reveals apple domains form a disk shown opposite and the positions of mutations identified in patients with FXI-deficiency patients that involve buried residues are green or surface exposed residues in red.

The role of contact proteins and FXI in hemostasis and thrombosis.

Thrombotic disorders are the most common causes of morbidity and mortality in the western world. A number of lines of evidence suggest that FXII, FXI, PK are superior targets to extrinsic pathway proteases, such as thrombin and FXa, as they should have reduced or no bleeding side effect. Knockout studies in mice have shown that loss of contact proteins or FXI results in a similar reduced thrombus formation in models of the disease without bleeding. Human genome wide studies report associations of single nucleotide polymorphisms in FXII, FXI, PK and HK with thrombosis and variation in the aPTT coagulation test. Humans with FXI deficiency have been shown to be protected from deep vein thrombosis and individuals with elevated FXI levels have a higher risk of ischaemic stroke .

 

A project towards safer anticoagulation.

Current anticoagulants such as heparin and warfarin have many drawbacks including the requirement for continuous monitoring and bleeding side effects. Newer agents dabigatran and rivaroxaban are small molecules which target proteases thrombin and factor Xa (FXa) respectively and represent an improvement as anticoagulant small molecule therapies. However both these agents target the extrinsic pathway and the initiation of the coagulation cascade and hence also have the potential to cause a bleeding side effect. Currently there are no anticoagulant therapies which target the intrinsic pathway higher up the coagulation cascade and a wealth of evidence now suggests that new therapies in this area could provide a safer, milder form of anticoagulation. Cardiovascular diseases such as stroke are more sensitive to bleeding side effects of anticoagulant agents and this can have fatal consequences for patients receiving these treatments.

The safer anticoagulation project at The University of Nottingham has received a major funding boost through grant awards from the British Heart Foundation. Grants totalling more than £1.3m have been awarded to the  School of Pharmacy and are aimed at gaining a deeper understanding and selectively targeting coagulation X factors (FXII and FXI) from the blood’s contact system.

The contact system recognizes foreign surfaces (including bacteria) whereby it subsequently becomes activated triggering a number of processes involved in the regulation of haemostatic and inflammatory processes.  These include: the release of the nano-peptide bradykinin (which can affect changes in blood pressure), release of anti-bacterial peptides, and the activation of blood coagulation. Recent research in the last five years has shown that inappropriate activation of the contact system can be linked to serious health problems such as heart disease or stroke.

Disease models of stroke have shown a significant role for activation of ‘X factors’, which seem to be central to the pathology of the disease. Thus factor XII and factor XI are of great therapeutic interest in the drive to discover novel anticoagulant therapies. 

This project was initiated by Professor Jonas Emsley and benefits from collaborations with Professor Philip Bath (Division of Stroke Medicine, University of Nottingham) who is an expert in clinical trials and the treatment of stroke and the groups of Professor Peter Fischer and Dr Lodewijk Dekker have expertise in drug discovery and have developed a platform for developing new medicines within the School of Pharmacy.

Drug design methodology is based on high resolution structures determined using protein crystallography by the group of Jonas Emsley. Also vital to the project is The University of Nottingham’s fully automated state-of-the-art Managed Chemical Compound Collection (MCCC) with more than 80,000 compounds for high through-put screening. This facility is key for identifying lead compounds capable of inhibiting the activity of coagulation factors. 

Key research article:

(1) Structure and function of factor XI. Emsley J, McEwan PA, Gailani D.

Blood. 2010 Apr 1;115(13):2569-77.

 Factor-XI-new
 Structure
 

 

Thrombotic disorders are one of the most common causes of morbidity and mortality in the western world. Knock out studies in mice have shown that a loss of contact proteins result in reduced thrombus formation without bleeding. Human genome wide studies have demonstrated an association between single nucleotide polymorphisms in contact proteins (FXII, FXI, PK, HK) and thrombosis as well as variation in the activated partial thromboplastin time (aPTT). Humans with FXI deficiency have shown to be protected from deep vein thrombosis while individuals with elevated FXI levels are predisposed to a higher risk of ischaemic stroke.

New Treatments for Cardiovascular Disease:

Both FXI and PK have been validated as targets for the development of new treatments for cardiovascular disease. A number of lines of evidence suggest that therapeutic intervention in which contact proteins are targeted, has the potential to reduce thrombus formation without compromising haemostasis – a major breakthrough in anticoagulant therapy.

 BHF

British Heart Foundation

Coronary heart disease is the UK’s single biggest killer. For over 50 years we’ve pioneered research that’s transformed the lives of people living with heart and circulatory conditions. Our work has been central to the discoveries of vital treatments that are changing the fight against heart disease. But so many people still need our help. From babies born with life-threatening heart problems to the many mums, dads and grandparents who survive a heart attack and endure the daily battles of heart failure, every pound raised, minute of your time and donation to our shops will help make a difference to people’s lives. For more information, visit

www.bhf.org.uk

 

Structural Biology

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