Trypanocidal drugs targeting PFK and PYK

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

Protozoan parasites are the cause of serious diseases of the developing world where literally millions of people are at risk and tens of thousands die annually. Current treatments are poor and use very toxic drugs. The parasites have a rather unique biochemical pathway for metabolising sugar. We have characterised two proteins involved in this pathway and have used this information to design and synthesise libraries of drug-like molecules that block the pathway. Our initial trials also show that some of these compounds kill the parasite and show specificity against the parasite compared to mammalian cells. These results provide an excellent starting point for developing more potent and specific molecular families that can be tested as potential drugs. Our approach will lead to two complementary drug families that may provide the basis of a combination therapy that would not only be more potent, but also minimise the risk of the development of resistance in the parasite population.

Technical Summary

The parasitic protozoa Trypanosoma and Leishmania are the causative agents of several disabling diseases including sleeping sickness and Chagas? disease. Enzymes in the glycolytic pathway of these parasites provide a series of validated drug targets. We have recently solved the X-ray structures phosphofructo kinase (PFK) and pyruvate kinase (PYK) which have been shown by RNAi experiments to be absolutely required for parasite viability. The major aim of this project is to further develop two families of nanomolar drug-like inhibitors: one set of compounds will block the active site of parasite PFK and the second family will block the allosteric site of parasite PYK. These two targets are ideally complementary as both families of inhibitors have similar chemical characteristics. Three chemical libraries of furanose-like PFK and PYK inhibitors have been synthesized and a number of specific inhibitors have been discovered with IC50 values between 20 and 100 ?M. Significantly the current lead compounds kill parasites with ED50 values as low as 30?M and show up to 95% specificity for inhibiting parasite PFK over mammalian enzymes. Structure-based studies using our newly determined X-ray structures suggest the design of modified libraries with enhanced binding and specificity. The project will build on these structure-based and combinatorial chemistry results to develop medically relevant inhibitor families that may provide the basis of novel mono or combination therapies.

Publications

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publication icon
Morgan HP (2010) An improved strategy for the crystallization of Leishmania mexicana pyruvate kinase. in Acta crystallographica. Section F, Structural biology and crystallization communications

 
Description NIH Molecular Libraries Roadmap Initiative
Amount £25,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 06/2009 
End 06/2011
 
Description NIH roadmap
Amount £30,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 06/2011 
End 06/2013
 
Title EDULISS 
Description Database searching tools for the discovery of small molecule ligands 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2008 
Provided To Others? Yes  
Impact The preexisting database Eduliss contains 5M commercially available compounds. FOr this project a set of pharmacophore searching tools were develeped and used successfully. They are now freely available on the web. http://eduliss.bch.ed.ac.uk/eduliss/ 
URL http://eduliss.bch.ed.ac.uk/eduliss/
 
Description NIH roadmap 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Phosphoglycerate mutase screening program at NIH Maryland
Collaborator Contribution Screening of 300000 compounds against target enzyme
Impact An R03 grant was funds. Full screening will be complete in 2011 and compounds will be available for testing
Start Year 2010
 
Description Clan Sutherland Magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article by LAF-G entitled ?In search of a cure for sleeping sickness? in the biannual magazine published by the Clan Sutherland Society of Scotland.

discussion
Year(s) Of Engagement Activity 2009
 
Description College of Humanities and Social Sciences presentation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 26 August 2009 Presentation by LAF-G entitled ?Drug discovery for trypanosomiasis and other related diseases? at a joint meeting for members of the Centre for Infectious Diseases and colleagues in the College of Humanities and Social Sciences.

Interested discussion
Year(s) Of Engagement Activity 2009
 
Description Press Gang 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact LAF-G founding convener and then member of the Press Gang of the School of Biological Sciences (SBS). This Press Gang is a volunteer group of undergraduates, postgraduates, postdoctoral fellows and academics that are active in several areas related to the dissemination of research in SBS to the wider communities. Members of the Gang identify and prepare news items and liaise with the Press Office; launch regular BioPOD podcasts; encourage participation in outreach work in schools, festivals, exhibitions etc, and prepare material for the University Bulletin, Bionews, SBS website.

Members of the Gang identify and prepare news items and liaise with the Press Office; launch regular BioPOD podcasts; encourage participation in outreach work in schools, festivals, exhibitions etc, and prepare material for the University Bulletin, Bionews, SBS website. The SBS Press Gang was the first to be created at the University of Edinburgh, and its success has meant that it has subsequently been copied by other Schools within the University.
Year(s) Of Engagement Activity 2007