Research Group: Molecular Diagnostics and Therapeutics
Chemistry at the University of Southampton has an international reputation in molecular diagnostics and therapeutics and collaborates with teams in Medicine, Human Genetics, Optical Engineering, Electronic Engineering and Physics and Life Sciences to develop novel diagnostic and therapeutic approaches. This builds upon an area of significant reputation and know-how that is unique to Southampton. Chemistry has a long track record of working closely with the above groups and also with industrial diagnostics and therapeutics partners.
Currently Active: Yes
Recent developments in the field of genomics are leading to rapid advances in our understanding of gene regulation, gene expression and development. There are many emerging opportunities for scientists engaged in the molecular sciences on the interface between chemistry and biology. Key areas of interest include the following.
Highly parallel high-throughput methods of DNA sequence analysis
Highly parallel high-throughput methods of DNA sequence analysis, particularly those that allow direct sequencing of modified bases such as 5-methyl dC and 5-hydroxymethyl dC are of great interest. 5-MedC is the “fifth base” in human genomic DNA and the biomedical implications of sequencing all five bases in DNA are immense. In the therapeutic area, methods to switch methylation of DNA on or off form a key basis for drug development. Other potential molecular genetic switches include quadruplex formation. There is some very important fundamental science to be done in this area.
Point-of care diagnostic
Rapid feedback diagnostic procedures for bacterial or viral infections that can be used in the clinic are of great value. DNA-based methods are being developed to allow diagnosis and treatment in a single visit to a GP. This area requires new detection technologies and will greatly benefit from collaboration with Medicine, the Wessex Regional Genetics laboratory, ECS and the Optoelectronics Research Centre. The technology will be generic, and therefore applicable (for example) to MRSA and animal and plant diseases.
Related to the above, rapid sequence-specific methods of genetic analysis are important in pharmacogenomics. A number of candidate drugs have failed in clinical trials because of side-effects and it is becoming apparent that these problems can often be predicted from the genetic make-up of an individual. This means that when the genotype is known, a drug can be used safely in a predictable way. In the same area, new rapid analytical methods to determine the molecular genetics of cancer cells could be used to determine the most appropriate therapy. In vivo diagnostics using highly sensitive fluorescence-based methods is an emerging field. Microfluidics will be an important element of some of the above technologies. The ability to multiplex assays for disease markers will dramatically increase the speed and reliability of disease diagnosis and will require the integration of analytical (bio)-chemistry and nano-scale devices. Recent work in the field (Brown group) involves developing methods of genetic analysis.
Natural and synthetic small molecules
The use of natural and synthetic small molecules as chemical probes to study and understand biological processes in vitro and in vivo is the objective of numerous collaborations between the Schools of Chemistry and Medicine. These investigations encompass all stages of the drug discovery process. Targets for next-generation therapeutic agents are being explored and validated including kinases, metalloenzymes, calcium signalling and tumour antigens.
At the other end of the spectrum, collaborations have resulted in licensed patents and clinical trials that are currently scheduled for cancer, psoriasis and fibrosis. Modulators of epigenetic enzymes are intensively studied within the school (Ganesan) and in collaborations with the School of Medicine. Examples include methyltransferases, acetyltransferases, demethylases and deacetylases. This activity has resulted in the creation of a spinout, Karus Therapeutics. Karus has received £750,000 in seed financing - a record for the university. The School has founded an EU-wide network via the COST Action ‘Epigenetics: From Bench to Bedside’.
Selective inhibition of medically relevant protein-protein interactions
The selective inhibition of medically relevant protein-protein interactions is a novel means to combat diseases such as cancer and HIV on a genetic level with small molecules that disrupt protein-protein interactions that are vital for the disease state. Collaborations (Tavassoli) with the Cancer Research Centre at Southampton General Hospital are proving important in this area. Related to this is the development of novel enzyme inhibitors as anti-bacterials and new protein labeling technologies for in vivo imaging applications.
Lipid-binding proteins play key roles in diverse physiological processes, such as gene regulation, signalling, membrane trafficking, lipid metabolism and transport, and the immune response. The lipid–protein interaction occurs via hydrophobic interactions, often within a lipid binding groove. Modification of the lipid to improve affinity is difficult, mostly for steric but also for electronic reasons. New approaches to achieve this goal will be of fundamental importance, and collaboration with computational chemists and immunologists will be important to develop lipid-based compounds with increased affinity based on conformational control and weak attractive interactions. Likewise, carbohydrates play a fundamental role in many physiological processes. However, carbohydrate-based therapeutics typically suffer from low affinity to proteins due to the extensive hydration in aqueous solution. Heavily fluorinated carbohydrates are carbohydrate mimetics, with expected increased affinities due to the so-called ‘polar hydrophobicity’ effect. There is great scope for the investigation of such compounds with biological collaborators. The Linclau group is engaged in this molecular diagnostics and therapeutics research.
Members of staff associated with this group:
Professor George S Attard
Professor Tom Brown
Dr Seung Seo Lee
Dr Bruno J Linclau
Dr Sumeet Mahajan
Dr Iris Nandhakumar
Professor Peter L Roach
Dr Eugen Stulz
Dr Ali Tavassoli
Dr Jonathan K Watts
Research projects associated with this group: