PhD Studentship: Design and Characterisation of Bioportides to Modulate Stem Cell Differentiation

Project Description:

Cell penetrating peptides (CPPs), composed of amino acids and synthesized in a laboratory, are a versatile way to effectively deliver medicines into human cells. Some CPPs, named bioportides, are also biologically active and can themselves act as a drug. Of relevance to this project, selected bioportides which mimic important segments of proteins found throughout the animal kingdom, can enter stem cells to influence the formation of complex tissues. This is important because stem cells play a major role to generate all other specialized cell types in the human body. By improving the design and properties of bioportides, this project will, therefore, support therapies to treat unmet medical needs including spinal injuries, Parkinson’s disease, and cancer. 

PhD investigations will focus upon the design, synthesis, and characterisation of bioportides able to influence the fate of stem cells and with properties like conventional drugs. A detailed survey of proteins that regulate the function of stem cells will identify new targets, vital for stem cell function, and potentially modified by bioportides. The identification of very efficient CPP sequences, and potential bioportides, will utilise a newly developed machine learning computer programme. Synthesis of these novel sequences will incorporate structural modifications to enhance their effectiveness within the human body. A range of biochemical and cellular assays will subsequently select those compounds most suitable for further evaluation as drugs and define their mechanism of action.

In addition to the training of a successful PhD studentship, this project will further support the establishment of a core peptide synthesis facility at BCU. Once in place, this facility will promote additional research collaborations, establish links with industry, and provide innovative projects for other students.

Anticipated Findings and Contribution to Knowledge:

In common with the dominant negative action of many bioportides, it is likely the primary mode of action of examples able to modulate stem cell function is the inhibition of discrete protein-protein interactions. For example, both [Aib13]Djeya1 and [Aib16]Djeya1 seemingly interfere with PPIs mediated by the highly conserved ED domain of Eya proteins. PhD investigations will further define a mechanism of action of bioportides, information to be utilised in the design of second-generation compounds with more drug-like properties.

Knowledge of temporal interactomes which contribute to neoblast fate will identify additional PPIs amenable to bioportide technologies. Detailed characterisation of synthetic peptides containing sequences to mimic these conserved domains will provide materials capable of influencing human stem cell fate. The same studies will identify the most appropriate structural modifications to engineer bioportides with a more drug-like pharmacokinetic profile.

Related studies will seek to develop the first examples of bioportides which modulate protein:DNA interactions. Such studies could enable the discrete modulation of one or more of ~40 transcription factors, expressed in the various subsets of planarian neoblasts, but also involved in human tissue formation.

This project will, therefore, generate significant new knowledge specifically relating to bioportide technologies and stem cell differentiation. Moreover, the programme will also increase understanding of protein-protein interaction modulators, a current emphasis within the pharmaceutical industries seeking new strategies for drug development.

Contact (and Director of Studies for this project): Prof John Howl - [email protected]