Target Identification of the AWOL based Macrofilaricide Drug Candidate AWZ1066

Over a 7 year period we have undertaken a Wolbachia based macrofilaricide drug discovery project. After screening >2M compounds we have carried out a lead optimisation project on an Azaquinazoline based core to generate AWZ1066 as a candidate molecule for onward progression against an accepted TCP. The mechanism of action of 1066 is currently unknown. We will adopt a chemical biology probe based pull down/ LCMS approach to identify the targets of AWZ1066.

 Where does this project lie in the translational pathway? 
 This is an FDA requested element of the IND filing package alongside the formal pre-clinical data pack and CMC

Methodological aspects of the PhD project

The project will focus on LCMS based semi-quantitative proteomics of probe tagged proteins from Wolbachia. The student will need to be able to handle large and complex peptide databases, reconstruct and formally ID protein targets by manual and computer aided approaches and be able to analyse the statistical relevance of the proteins identified.

Expected outputs of the PhD project

Meachanism of action studies usually generate high impact publications and confirmation of a validated target will be central to obtaining further funding to investigate the underlying biochemistry associated with the target as well as target based hit ID screening initiatives.

External industry links or training opportunities available for the student

We already have an industrial partner supporting the discovery elements of the project, Eisai Pharma, and the student will spend time within their US labs developing skills in proteomics and LCMS based target identification techniques.

Required skills/experience/aptitudes 

1st/2i degree in biological/chemical sciences with a preference for pharmacology/biochemistry based disciplines. Experience in MS based analytic methods would be helpful.

Key publications that relate to this proposed project

1.

Aljayyoussi G, Tyrer HE, Ford L, Sjoberg H, Pionnier N, Waterhouse D, Davies J, Gamble J, Metugene H, Cook DA, Steven A, Sharma R, Guimaraes AF, Clare RH, Cassidy A, Johnston KL, Myhill L, Hayward L, Wanji S, Turner JD, Taylor MJ, Ward SA. (2017) Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis. Sci Rep. 2017 Mar 16;7(1):210. doi: 10.1038/s41598- 017-00322-5.

2.

Aljayyoussi G, Jenkins VA, Sharma R, Ardrey A, Donnellan S, Ward SA, Biagini GA.(2017) Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration. Sci Rep. 2017 Mar 29;7(1):502. doi: 10.1038/s41598-017-00529-6

3.

Ismail HM, Barton VE, Panchana M, Charoensutthivarakul S, Biagini GA, Ward SA, O'Neill PM. (2016) A Click Chemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile. Angew Chem Int Ed Engl. 2016 May 23;55(22):6401-5.

4.

Raman Sharma, Ghaith Al Jayoussi, Hayley E. Tyrer, Joanne Gamble, Laura Hayward, Ana F. Guimaraes, Jill Davies, David Waterhouse, Darren A. N. Cook, Laura J. Myhill, Rachel H. Clare, Andrew Cassidy, Andrew Steven, Kelly L. Johnston, Louise Ford, Joseph D. Turner, Stephen A. Ward & Mark J. Taylor (2016) Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis. Sci Rep. 2016 Mar 21;6:23458. doi: 10.1038/srep23458

5.

Hanafy M. Ismail, Victoria Barton, Matthew Phanchana, Sitthivut Charoensutthivarakul, Michael H. L. Wong, Janet Hemingway, Giancarlo A Biagini, Paul M. O’Neill, and Stephen A. Ward (2016) Artemisinin Activity Based Probes Identify Multiple Molecular Targets Within the Asexual Stage of the Malaria Parasites Plasmodium falciparum 3D7 Proc Natl Acad Sci U S A

 

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