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Fostering development of ‘smart’, responsive therapeutics against cancer-related microRNAs.


Project Description

Short functional non-coding microRNAs are implicated in many types of cancer, and thus can be used as biological targets for development of more selective and powerful anticancer therapies. MicroRNA mediated silencing is recognised therefore as a promising alternative to the conventional approaches that are traditionally based on treatment of physiological abnormalities at the level of expressed proteins and which often suffer from adverse drug reaction and toxicity.
This project focuses on the development of synthetic peptide-oligonucleotide hybrids1-4 for selective targeting of highly oncogenic microRNA sequences with distorted expression profiles. These chemically-engineered RNA-targeting molecules will be generated by conjugation of short, catalytically inactive peptides with DNA recognition motifs to produce novel biologically-active molecules capable of recognising and cleaving cancer-related microRNAs. The most remarkable feature of these ‘intelligent’ molecules is that conjugation of peptide and oligonucleotide building blocks synergistically combines the individual properties of the two components, and yields a new, hybrid molecule with unusual catalysis, capable to recognise microRNA, ‘cleave and leave’ the destroyed sequence, in order to attack and inactivate the next RNA molecule.
This coordinated cross-disciplinary project will be carried out at the interface of chemical biology, biophysics, molecular modelling and drug delivery1-5. The design of this type of novel therapeutics will be based on a synergetic combination of the detailed 3D structural data (to be gained from molecular modelling) and novel chemical strategies for site-directed conjugation. To demonstrate a proof-of-principle at this early-phase development, we shall evaluate hybridisation and cleavage abilities of our constructs against established panel of cancer-relevant microRNA sequences in collaboration with Prof. Marina Zenkova (Institute of Chemical Biology & Fundamental Medicine, Novosibirsk, Russia) and Dr. Michela Garofallo (Manchester Cancer Research Institute, UK). The peptide structure will be systematically varied to provide a future platform for selective targeting diseased tissue and facilitate transport across biological barriers5.

Training/techniques to be provided:
The training will be provided at the interfaces between structural biology, chemistry, biophysics and molecular modelling. The recruited PhD student will benefit from established collaborations to develop research expertise across chemical biology, molecular simulation and modelling, structural biophysics, drug delivery and translational medicine. This will encourage the recruited student to appreciate and value collaborative and coordinated multidisciplinary approaches necessary to resolve healthcare grand challenges. Given the breadth of biophysical science, computational and pharmaceutical chemistry skills provided, such training would support progression into a variety of career positions within academic or industrial settings involving pharmaceutical sciences, medicinal chemistry, nanoscience or biotechnology. Graduates with skills-sets spanning these areas are rare, so the training would provide a solid platform for career development.

Entry Requirements:
Applicants should hold (or expect to obtain) a minimum upper-second honours degree (or equivalent) in chemistry, biochemistry, biophysics or relevant physical sciences subject with previous experience in chemistry, analytical and spectroscopic techniques. They must also be capable of working at the interface between chemistry, biology and biophysics. Some experience in computational chemistry would be highly beneficial. A Masters qualification in a similar area would be a significant advantage.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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