Synthesis of Novel Inhibitors of Parasite Motility: Medicinal Chemistry Applied to a Life-Threatening Brain Infection

Project Description

The Disease We Are Hoping to Cure:

Toxoplasmic encephalitis (TE) is a life-threatening brain infection of AIDS patients caused by the opportunistic protozoan parasite, Toxoplasma gondii. Within the brain and other tissues of a patient suffering from this disease, the destructive tachyzoite stage of the parasite uses a unique form of substrate-dependent “gliding” motility to invade into and burst out from the cells of its host, to migrate across biological barriers and to disseminate through the infected host’s tissues.

Background to The Project:

Over many years, the Westwood group, in collaboration with Professor Gary Ward at the University of Vermont, USA, has been studying compounds that block tachyzoite gliding motility. If parasites cannot move they cannot invade cells and cause disease. Our expertise in organic synthesis has helped the optimisation of the biological activity of screening hits and enabled the preparation of new reagents for target identification studies. Please see examples of some of our published work in the references section.

In general our part of the research has involved the synthesis of families of analogues in specific heterocycle-containing core structures.

The New Project:

We have funding to study some new hits that have just been identified. High level skills in organic and medicinal chemistry and chemical biology will be developed as we carry out structure-activity relationship studies. A wide range of reactions for the synthesis of chiral compounds in highly enantiomerically enriched forms will be required. This will require skills in reaction design, set-up, monitoring, work-up, compound purification and analytical chemistry especially NMR. If you are interested in a synthesis project with a chemical biology/medicinal chemistry goal then this could well be the project for you. Please get in touch as soon as possible.

Funding Information

This project is fully funded for 3.5 years covering both stipend and fees (including the international fee component if required).

There are funds for international travel.

Key criteria for recruitment include:

  1. core interest in synthetic chemistry applied to chemical biology / medicinal chemistry projects
  2. skills in all aspects of organic synthesis
  3. experience of working in interdisciplinary research projects

References

The following are examples of the interdisciplinary publications that have resulted from the Ward/Westwood collaboration

  1. Using small molecules to study big questions in cellular microbiology Cellular Microbiology (2002), 4(8), 471-482.
  2. A small-molecule approach to studying invasive mechanisms of Toxoplasma gondii Proceedings of the National Academy of Sciences of the United States of America (2004), 101(19), 7433-7438.
  3. Synthesis and chemical characterization of target identification reagents based on an inhibitor of human cell invasion by the parasite Toxoplasma gondii Organic & Biomolecular Chemistry (2007), 5(13), 2063-2069.
  4. Synthesis and biological evaluation of functionalised tetrahydro-β-carboline analogues as inhibitors of Toxoplasma gondii invasion Organic & Biomolecular Chemistry (2009), 7(15), 3049-3060.
  5. A Modular Approach to Triazole-Containing Chemical Inducers of Dimerization for Yeast Three-Hybrid Screening Molecules (2013), 18(9), 11639-11657.
  6. Identification of T. gondii myosin light chain-1 as a direct target of tachypleginA-2, a small-molecule inhibitor of parasite motility and invasion PLoS One (2014), 9(6), e98056/1-e98056/13

To apply for this PhD, please email njw3@st-andrews.ac.uk.

Before sending your email, please double check you have followed all guidelines in this listing and have included a reference number if asked to do so.

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