My main research focus is to develop innovative diagnostics and therapeutics through fabrication of functional biomaterials with desired biological properties and controlled functionalities using natural biomacrmolecules (e.g. peptides and nucleic acids) as building blocks. The most important contributions from my research to date include the developments of novel nucleic acid diagnostics and therapeutics to solve biomedical grand challenges, currently unmet by traditional Drug Discovery & Development approaches.
Molecular diagnostics for potential biomedical and clinical applications
I have previously contributed to the development of small-molecule diagnostic tools for detection of physiological stimuli as potential biomarkers for signalling of tissue abnormalities. Our most recent development includes self-assembling peptidyl-oligonucleotide hydrogels for molecular diagnostics, which offers a 3D sensing capacity and provides a large analyte reservoir thereby enhancing sensitivity and decreasing the detection limits. The controlled self-assembly of individual components into desired 3D nano-architectures is guided by structural biology methods and can be precisely engineered by manipulating the chemical structures of building blocks thus leading to a step-increase in improvement of reliability, accuracy and quality assurance.
Development of novel therapeutic strategies
We have recently developed synthetic catalytic biomaterials capable of recognising and selectively destroying RNA, thus targeting the emerging importance of regulatory RNAs in disease pathways, in order to switch intracellular, paracrine and endocrine signaling pathways from ‘diseased’ to ‘normal’. These advances are particularly beneficial for such biological targets that are not amenable to small-molecule drugs due to the lack of suitable binding sites for small molecules, and also unsuited to large molecule drugs (such as monoclonal antibody inhibition) due to their intracellular location (e.g. transcription factors).
Through our well-established international collaborations, we have recently provided the first experimental evidence that our chemically-engineered peptidyl-oligonucleotide bio-conjugates cleave and silence miR-21 in lymphosarcoma. Our structural insights into the interactions between these DNA-peptide hybrids and miR-21 will guide future design of such conjugates and accelerate translation of our research outcomes to future therapeutic applications. This discovery of highly-selective bio-mimetics against pathogenic microRNAs over-expressed in disease states opens up a new therapeutic window for drug discovery and provides a world-leading platform to advance development of new therapeutic interventions.
SENIOR INTERNAL EXAMINER
For the following units in the curriculum within the Pharmaceutical & Medicinal Chemistry disciplines (since 2011):
PHAR10100 'THE MEDICINE' (Y1)
PHAR20100 'THE MEDICINE' (Y2)
PHAR30100 'THE MEDICINE' (Y3)
PHAR PHAR20302 ‘BIG KILLERS’ (Y2)
PHAR30400 INTEGRATED RESEARCH SKILLS (Y3)
PHAR40100 'MEDICINE INTO PRACTICE' (Y4)
PHAR10102 ‘PROPERTIES OF MEDICINES’
Y 1 Integrated Exam
Y1 Consolidated Exam
Y2 Integrated Exam
Y2 Consolidated Exam
This role involves reviewing the exam papers, organising and chairing the exam moderation boards for the "MEDICINE" strand (3 per year), liaison with external examiners and unit leads regarding the final versions of the assessment, attending UG Teaching & Learning committee meetings and liaison with external examiners during their annual visits.
The role of PGR tutors and advisor (to oversee 32-34 PGR students/year) is to form an oversight network within the School to ensure consistent, reliable assistance, recruitment and supervision of all PGR students in the School (in addition to my roles as an academic supervisor and advisor). PGR tutors are now expected to be involved in individual Skype interviews of each potential PhD applicant.
NMR AND OPTICAL EQUIPMENT
1. Supervision and management of the School’s NMR equipment.
This includes full responsibility for the 300 MHz and 400 MHz spectrometers (Bruker) as well as Pharmacy’s use of the shared 500 MHz spectrometer located in the School of Chemistry, involving:
(i) Supervision of the instruments as well as NMR users (25-30 research users).
(ii) Coordinating training for new NMR users.
(ii) Organisation and management of NMR accounts.
(iv) Spectrometer troubleshooting and routine maintenance (e.g. cryogenic filling on a weekly basis).
2. Supervision and management of the School optical spectroscopy equipment.
Responsibility for the optical spectroscopy facilities (co-applicant BBSRC, Wolfson and EPSRC): two UV-visible, two fluorescence instruments plus 2 x 96-well UV-visible absorption / fluorescence plate reader instruments, FTIR and picosecond lifetime fluorescence. My role includes supervision, maintenance and repair of the instruments and organising training and access for the staff and students users.
Structural aspects of peptidyl-oligonucleotide chemical ribonucleases
The main focus of our EPSRC funded research was the development of highly specific, synthetic enzymes capable of damaging RNA. The design of novel biocatalytic supramolecular structures mimicking the active centre of natural ribonucleases and capable of cleaving RNA targets can provide a basis for generating new useful biological tools and even powerful therapeutics, affecting specific messenger RNAs and viral genomic RNAs.
In the frame of our collaborative work with Russian colleagues, a new type of chemical ribonucleases with unusual biological and catalytic properties has been developed. These novel compounds were constructed by chemical conjugation of short, synthetic peptides with oligonucleotide fragments. The most remarkable feature of these novel catalytic molecules was that the oligonucleotide mediator enormously enhanced the biological activity of a previously inactive peptide. However, the basic and fundamental processes behind this unusual discovery have never been studied. Therefore, the main focus of our research supported by EPSRC was to provide an understanding at the molecular level of how these functionally significant entities interact with each other and mutually modulate their activities.
The aim of our EPSRC funded research therefore was to determine the structural rules and molecular mechanisms, which govern biological activity of these novel synthetic catalysts and assess whether they can recognize and specifically cleave biologically significant RNA sequences. To achieve this we used various high-resolution NMR structural studies in combination with high-level computational approaches. The results of our research have shown that the merger of two chemical entities (short peptide fragment and synthetic oligonucleotide sequence) seemed to produce a new, hybrid-type of molecule that could synergistically combine the individual properties of the two components to yield a new and unusual biological ability. The oligonucleotide component seemed to induce an `active` structure of the peptide moiety and hence significantly enhance its catalytic performance.
The labelling of these synthetic enzymes with fluorescent tags allowed us to monitor their interactions with RNA sequences, which seemed to be driven by strong non-specific electrostatic interactions and/or by highly specific Watson-Crick hydrogen-bonding.