Accelerating early-phase development of novel therapeutic interventions: 'intelligent' anti-cancer agents against oncogenic microRNAs.

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Project Outline. This research aims to develop novel therapeutics to target and irreversibly destroy pathogenic, cancer-relevant microRNA molecules via controlled molecular self-assembly and precise sequence recognition of unique RNA sequences. The catalytic nature of these highly-selective bioconjugates will allow us to enhance the efficiency of future therapeutic treatments and minimise undesirable off-target effects. 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, long non-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 cancer, 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 hybrids 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. The key challenge of this research will be to develop a new generation of conjugates that combine precise sequence-specificity of RNA cleavage with enhanced catalytic turnover to achieve high efficiency and reduce off-target effects.Proposed research plan. This coordinated cross-disciplinary project will be carried out at the interface of chemical biology, biophysics, structural biology and drug delivery. The design of this type of novel therapeutics will be based on a synergetic combination of the detailed 3D structural data (previously obtained from NMR spectroscopy and 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. The success of this research will offer superior therapeutic interventions with improved potency, lower dosage and reduced toxicity. We anticipate that the key outputs of this research will provide a basis for enhanced efficacy of future anticancer therapeutics and reduced risk to patients.