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Drug discovery and Chemical-Biology Approaches Against Parasites that cause Neglected Tropical Diseases.

  • Full or part time
  • Application Deadline
    Friday, December 14, 2018
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

This proposal is aimed at students wanting to work at the interface of chemistry and biology.
You will undertake both the chemical synthesis of substrate analogues as potential inhibitors and then also the biological testing both in vitro and in vivo of “in house” genetically validated drug targets against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp the causative agents of Neglected tropical diseases.

Scientific Background:
Trypanosomatid protozoan parasites of the Trypanosoma and Leishmania genera cause widespread disease and death across large regions of the developing world. Trypanosoma brucei, Trypanosoma cruzi and several species of Leishmania cause human African trypanosomiasis (HAT) in sub-saharan Africa, Chagas disease in south and central America, and leishmaniasis throughout the tropics and sub-tropics respectively, where they are transmitted by infected arthropod vectors. Collectively, there are an estimated 1 million new infections annually and hundreds of millions are at risk of infection.1-3 Disease severity is dependent upon the infecting parasite: HAT is almost invariably fatal within 3 years if left untreated, as blood-borne T. brucei invade the central nervous system and brain, causing encephalitis;1 Chagas disease typically forms a chronic infection of cardiac and digestive muscle tissue which, in 30% of cases, leads to cardiomyopathy and premature death through progressive heart failure, stroke or aneurysm;2 while leishmaniasis is typically an acute infection of cutaneous or mucocutaneous tissue, resulting in life-long scarring and serious disability,3 or infection of the spleen and liver (visceral leishmaniasis), which is fatal if untreated. In addition, all three parasite genera can infect and cause disease in domesticated livestock and wild animals, which in some situations forms a reservoir for human infections,1-2,4 and harms the agriculture industry in some of the World’s poorest and most deprived regions. There has been little investment/development of drugs to treat these neglected diseases and current therapies are antiquated, difficult to administer and are themselves harmful. Additionally, there is growing resistance to currently prescribed drugs,5 hence new therapies are urgently needed

Goal:
This exciting and cutting edge work will find and develop compounds that will become lead compounds that inhibit enzymes that we have already shown to be essential for these parasite, allowing them to be developed further towards usable drugs to cure these neglected diseases.
A better understanding of how the specific enzymes work and their structure and role within the metabolism of the parasites will be learnt, which will assist future research.

Research plan:
The student will undertake a wide range of chemical, biochemical and molecular techniques, including training in parasite culturing at Cat 3 level.
Chemical synthesis of substrate analogues.
Synthesis of probes as chemical probes to address biological questions.
Molecular biology allowing recombinant expression, purification and detailed kinetic analysis. Allowing substrate / inhibitor studies, high-through screening, and several in house biophysical techniques to study compound/protein interactions, including protein crystallography. Biochemical phenotyping of potential “on” target lead compounds will be varied and detailed utilising techniques such as metabolomics/ lipidomics as well as various labelling methodologies. Further genetic manipulation of the parasites, by various methods including CRISPR /Cas9 technologies will reinforce “on” target prognosis.

Funding Notes

Must already have experience in the lab and have a suitable degree.

References

1. WHO (2017). http://www.who.int/mediacentre/factsheets/fs259/en/.
2. WHO (2017). http://www.who.int/mediacentre/factsheets/fs340/en/.
3. WHO (2017). http://www.who.int/mediacentre/factsheets/fs375/en/.
4. Singh N et al. (2013). J Parasitol. 99:64-7.

How good is research at University of St Andrews in Chemistry?
(joint submission with University of Edinburgh)

FTE Category A staff submitted: 37.30

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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