About the Project
Significance and potential impact. A major biomedical challenge is highly-selective therapy against abnormal gene expression in disease states (e.g. cancer, inflammation) where combination therapies, including comparatively toxic drug cocktails, are otherwise indicated. Novel therapeutic strategies for selective treatment of disease states can be facilitated by targeting of upstream cellular components (e.g. messenger RNA, small non-protein-coding RNAs) to achieve controlled translational arrest of pathogenic proteins and thus trigger a desired therapeutic response. Indeed, short functional non-coding microRNAs are implicated in many types of cancer1-2, and thus can be used as biological targets for development of more selective and powerful anticancer therapies. RNA-mediated gene 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.
Aims of the project. This project focuses on the development of synthetic peptidyl-oligonucleotide hybrids3-5 for selective targeting of pathogenic RNA sequences (e.g. cancer-related microRNAs) 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 disease-relevant RNAs. The most remarkable feature of these 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 of cleaving RNA molecules under physiological conditions.
Proposed research plan. This coordinated cross-disciplinary project will be carried out at the interface of chemical biology (EB), biophysics (EB), computational approaches (RB), structural biology (EB, RB) and drug delivery (DC). 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 capabilities 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 main deliverable output of this project is to achieve a high level of reaction catalytic turnover (‘cleave and leave’) while retaining effective bio-specificity. The peptide structure will also be varied to provide a future platform for selective targeting diseased tissue and facilitate transport across biological barriers.
http://www.pharmacy.manchester.ac.uk/staff/ElenaBichenkova/
http://www.pharmacy.manchester.ac.uk/staff/DavidClarke/
http://www.pharmacy.manchester.ac.uk/bryce/
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
1. M.V. Iorio, R. Visone, G. Di Leva, et al., MicroRNA signatures in human ovarian cancer, Cancer Research, (2007), 67, 8699–8707.
2. A. Markou, I. Sourvinou, P.A. Vorkas, G.M. Yousef, E. Lianidou, Clinical evaluation of microRNA expression profiling in non-small cell lung cancer. (2013) Lung Cancer, 81, 388-396.
3. O.A. Patutina, E.V. Bichenkova, S. K. Miroshnichenko, N. L. Mironova, L. T. Trivoluzzi, K. K. Burusco, R.A. Bryce, V. V. Vlassov, M. A. Zenkova. miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells. (2017) Biomaterials, 122, 163-178.
4. Staroseletz, Y., Williams, A., Alibay, I., Burusco-Goni, K., Vlassov, V. V., Zenkova, M. A. & Bichenkova, E. ‘Dual’ peptidyl-oligonucleotide conjugates: role of conformational flexibility in catalytic cleavage of RNA. (2017) Biomaterials, 112, 44–61.
5. Williams, A., Staroseletz, Y., Zenkova, M., Jeannin, L., Aojula, H. & Bichenkova, E. Peptidyl-Oligonucleotide Conjugates Demonstrate Efficient Cleavage of RNA in a Sequence-Specific Manner. (2015) Bioconjug Chem, 26 (6), 1129-1143.