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MRC DiMeN Doctoral Training Partnership: The identification and optimisation of small molecule inhibitors of PfAPP as a novel antimalarial strategy


MRC DiMeN Doctoral Training Partnership

, Prof Elwyn Isaac Wednesday, January 27, 2021 Competition Funded PhD Project (Students Worldwide)
Leeds United Kingdom Biochemistry Organic Chemistry Pharmaceutical Chemistry Synthetic Chemistry

About the Project

Malaria poses a significant threat to approximately half of the world’s population with an annual death toll close to half a million. The emergence of resistance to front-line anti-malarials in the most lethal human parasite species, Plasmodium falciparum (Pf)threatensprogress made in malaria control and has made the development of novel antimalarial drugs a global health priority. Asexual reproduction of the parasite is critically dependant on the recycling of amino acids through catabolism of haemoglobin, which makes which makes metalloaminopeptidases (MAPs), and specifically aminopeptidaseP (PfAPP), an essential enzyme for parasite survival, an attractive target for the development of new drugs. Our pilot data has identified potent, low molecular weight chemical inhibitors of PfAPP which demonstrate encouraging biochemical potency. We will apply a multi-disciplinary approach to optimization of these inhibitors as effective anti-malarial agents. The identification of a potent, selective, and cell permeable inhibitor of PfAPP would be a significant advancement in our understanding of the potential for targeting PfAPP as an effective anti-malarial strategy.

Objectives:

1.     To demonstrate the ability to design and synthesize drug-like and potent inhibitors of PfAPP1

2.     To demonstrate the potential for incorporation of structural hypothesis to optimization through collaboration with University of Bath, Diamond Light Source and the Astbury Centre at Leeds for co-ligand structure determination and high-throughput fragment-based screening

3.     To optimise inhibitors for drug-likeness and pharmaceutical and pharmacokinetic properties consistent with a bioavailable antimalarial agent

The supervisory team share established track-records investigating the biochemistry, structural biology and design of chemical inhibitors targeting metallopeptidases. The lead supervisor has expertise in synthetic chemistry and design of metallopeptidasese inhibitors. The co supervisor has established in vitro and in vivo systems for PfAPP activity and through collaboration at University of Bath and the Astbury Centre at Leeds, the team has established structural biology for metallopeptidases . Pilot data has identified promising inhibitors of PfAPP1 demonstrating potent on-target inhibition, but which require optimisation for potency, selectivity (over the human form of APP1), cell permeability, and metabolic stability. 

We will resolve ligand bound X-ray structures using PfAPP to guide the design and synthesis of new compounds and development of structure activity relationships. We will characterise new compounds in vitro to inform the design and development of new compounds. Compounds will be profiled for pharmacokinetic properties to guide the design of cell permeable and orally bioavailable lead compounds. Innovative approach will be utilised to identify alternative starting points for lead optimisation through high-throughput fragment crystallography at Diamond Light Source. 

This work is expected to significantly increase the volume and quality of publications arising from our work in this area and to provide foundations for future translational studies developing novel anti-malarial agents targeting APP.

The project would suit a candidate interested in medicinal chemistry, organic chemistry, and the biochemistry of metallopeptidases

Lab website: https://foster.leeds.ac.uk/

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

Drinkwater, N., et al. Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum. Biochemical Journal. 2016, 473(19), pp. 3189-3204.

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