DiMeN Doctoral Training Partnership: Identification and optimisation of small molecule inhibitors of APP1 as novel therapeutics

Malaria is one of the world’s most prevalent parasitic diseases, with over 200 million cases annually. Alarmingly, the spread of drug-resistant parasites threatens the effectiveness of current antimalarials, and has made the development of novel therapeutic strategies a global health priority. Malaria parasites have a complicated lifecycle involving an asymptomatic ’liver stage’ and a symptomatic ’blood stage’. During the blood stage, the parasites utilise a proteolytic cascade to digest host haemoglobin, which produces free amino acids absolutely necessary for parasite growth and reproduction. The enzymes required for haemoglobin digestion are therefore attractive therapeutic targets. The final step of the cascade is catalyzed by several metalloaminopeptidases (MAPs), including aminopeptidase P (APP). Recent work has developed a platform to examine the substrate fingerprint of APP from P. falciparum ( Pf APP), and shown that it can catalyse the removal of any residue immediately prior to a proline. Further, we have determined the high resolution crystal structure of the human APP form and a recent disclosure of the Pf APP form, has provided structural basis for inhibition of this essential malarial enzyme. Together, these data provide insight into a potential mechanism of inhibition that could be used to develop novel antimalarial therapeutics.
The objective of this proposal will be to identify potent, soluble and cell permeable chemical tools as inhibitors of APP with potential to further validate the mechanism of inhibition and for further development into a therapeutic drug. Our strategy is to exploit the high-resolution structure of APP in a computational rational hit validation exercise to develop potent and cell permeable inhibitors. The aim will be to generate lead-like chemical probes that can be further developed into therapeutic agents. The project builds on existing strengths at the University of Leeds (UoL), combining expertise in small molecule hit identification and validation strategies and peptidase biochemistry and anti-malarial drug discovery with expertise in APP structural biology at UoL and University of Bath (UoB).
Fascinatingly, APP has also recently emerged as a target for development of anti-cancer agents. Chemical tools developed as anti-malerial agents during the course of the project will also be explored for their ability to be re-purposed for anti-cancer therapy as novel sensitising agents. We have excellent collaborations with groups at Imperial College to further develop this approach.

This studentship will aim to achieve the following objectives:
1. To demonstrate the ability to design drug-like and potent inhibitors of APP through traditional medicinal chemistry approaches and via techniques such as fragment-based screening.
2. To demonstrate the potential for incorporation of structural hypothesis to binding based on in silico design and aim to support this work through mutation studies and collaboration with others in the Astbury Centre at Leeds for co-ligand structure determination
3. To optimise the inhibitors for drug-likeness and pharmaceutical and pharmacokinetic properties consistent with a bioavailable agent
4. To validate the use of inhibitors in supporting the understanding of the link between APP and malaria, and also cancer

The project would suit a student with general interests in medicinal chemistry and drug design. The student will receive training in medicinal chemistry, and drug design (RF) as well assay design and biology of the target class (EI).

http://www.chem.leeds.ac.uk/richard-foster/welcome.html