Developing new anti-cancer drugs: computational design and chemoenzymatic production of modified cyclic peptide inhibitors of the oncogenic mortalin-p53 interaction at Aberdeen University on FindAPhD.com

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Dr Wael Houssen, Prof Anne Donaldson, Dr Sinclair Dundas, Dr Bruce Milne No more applications being accepted Competition Funded PhD Project (UK Students Only)

Aberdeen United Kingdom Biochemistry Bioinformatics Cancer Biology Cell Biology Computational Chemistry Molecular Biology Pharmaceutical Chemistry

About the Project

This drug discovery PhD project will involve computational design, chemoenzymatic synthesis and experimental testing of modified cyclic peptides engineered to function as potential chemotherapeutics. Specifically, we aim to interfere with cancer cell growth by inhibiting the oncogenic mortalin-p53 interaction. The broad profile of cancer types that over-express mortalin [1,2] suggests that novel anti-mortalin-p53 drugs could be clinically useful in many therapeutic contexts

Previous attempts to develop small molecule inhibitors for mortalin-p53 have been hampered by the lack of knowledge of the specific site of interaction between the two proteins and by nephrotoxicity that ended clinical trial testing [3]. However, growing evidence indicates that cyclic peptides surpass traditional small molecules in inhibiting disease relevant protein-protein interactions [PPIs] [4]. We have developed computational methods to design cyclic peptide inhibitors for PPIs [5] and effective chemoenzymatic approaches to produce constrained modified cyclic peptides [6].

In this project, the student will use these methods to computationally design modified cyclic peptides expected to function as highly specific mortalin-p53 inhibitors; and assay their potential as anti-mortalin / p53 reactivator drugs.

This studentship aims at:

1- Computational modelling of modified cyclic peptides designed to inhibit conformational changes within the mortalin’s substrate binding domain.

2- Chemoenzymatic synthesis of peptides.

3- Testing compounds’ ability to inhibit the PPi using Biacore-based assays

4- Using cell-based assays to evaluate the potential of newly-designed molecules to function as anti-tumour drugs.

5- Studying the structure-activity relationship and using the results to enhance compound activity.

Ideally, we seek an individual with a strong background in chemistry, biochemistry, and/or molecular modelling and drug design, and an interest in transferring their expertise towards improving cancer treatment strategies.

You will gain skills in state-of-the-art computational chemistry techniques, recombinant protein expression, synthetic peptide chemistry, in vitro biosynthesis and bioassay development. The supervisory team have extensive expertise in the required fields and their labs contain the necessary equipment for this type of work such as thermocyclers, automated microwave peptide synthesiser, FPLC and HPLC systems while the institute provides excellent core facilities including NMR and MS, imaging, microarrays, FACS, Biacore, and isothermal calorimetry. CFisUC hosts several advanced HPC systems which will be available for the project.

Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Funding Notes

This is a competition funded project including tuition fees and stipend at UKRI rates (for 2021-22. this is £15,609 pa). Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £17,000 per annum).
Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction as Master's level.

References

1- Wadhwa R et al. (2006) Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis. Int J Cancer 118, 2973.
2- Dundas SR et al. (2005) Mortalin is over-expressed by colorectal adenocarcinomas and correlates with poor survival. J Pathol 205, 74.
3- Wadhwa R, et al. (2000) Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res 60, 6818.
4- Villar EA et al. (2014) How proteins bind macrocycles. Nat Chem Biol 10, 723.
5- Idress M et al. (2020) Structure‐based design, synthesis and bioactivity of a new anti‐TNFα cyclopeptide. Molecules 25, 922.
6- Houssen WE et al. (2014) An Efficient method for the in vitro production of azoline-based cyclic peptides.” Angew Chem Int Ed 53, 14171.