Click Chemistry is a synthesis approach developed for the rapid construction of functional molecules, including new drugs, functional materials and important chemical tools for biology. By their very nature, Click reactions are high yielding, wide in scope, create only inoffensive by-products, are specific, simple to perform and can be conducted in easily removable or benign solvents. They enable the unification of discrete units or ‘building blocks’ in a controlled fashion, thereby building-up complexity with exquisite control. The Moses group focus on the development and application of new functional Click Chemistry, with particular emphasis on anticancer drug discovery, new antibiotics and chemical biology. For example, we have employed Click Chemistry in a number of drug discovery projects, including the development of therapeutic DNA binding ligands that interact with telomeric regions of the genome. This is important because telomere function is involved in cellular maintenance and is particularly relevant for cancer cell survival. We have made a number of telomere binding ligands, which show remarkable selectivity and potency against cancer cells. In another project, we developed the first fragment based Click Chemistry approach towards lactate dehydrogenase-5 (LDH5) inhibitors. LDH5 is an important metabolic enzyme, which is believed to be crucial for the survival of tumour cells and particularly those in an oxygen-starved environment. The LDH enzyme has two important regions in it’s active site, and we designed a molecule that can simultaneously bind to both sites and inhibit this key enzyme.
Antibiotic Drug Discovery
Anti-microbial resistance (AMR) is an emerging threat to human health, and one of the greatest challenges facing the world currently. According to the WHO: “A post-antibiotic era—in which common infections and minor injuries can kill—far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century”. Unfortunately, the problem is not improving, and no new antibiotic class has been developed in decades. The historical low cost and relatively short life-span of antibiotics have resulted in many companies moving away from antibiotic research due to poor economic return relative to investment. Traditionally, natural products have been the feedstock of new and diverse antibiotics (e.g. penicillins). However, the success of antibiotics is dependent upon their availability. Typically isolated in minute quantities from nature, the foundation of a sustainable supply is vital. This challenge is further compounded by the fact that many natural antibiotics are incredibly complex and sophisticated molecules, rendering them impractical for large scale synthesis. (see publications Chem. Eur. J. 2016) Rather than pinning all hopes on discovering new antibiotics; a process that is likely to take decades before they reach the clinic, a realistic short-to-medium-term solution is to re-engineer existing, readily available drugs such that they are not susceptible to existing resistance mechanisms. This approach will facilitate a “shortcut to the clinic” by fast-tracking toxicological and clinical trials given prior knowledge of the particular antibiotic class. In the Moses group, we are developing a novel approach to help fight anti-microbial resistance by employing Click Chemistry as a tool to reengineer antibiotics to overcome currently known resistance mechanisms
Biomimetic Synthesis of Complex Natural Products
Biomimetic chemistry is a synthetic approach towards the synthesis of natural products. It draws inspiration from the elegant higher order complexity-generating processes that ‘Mother Nature’ employs in her biosynthetic schemes — allowing rapid and efficient entry to complex core structures that may otherwise require lengthy and difficult schemes. The Moses group are pioneers in the field, and particularly in the development of concerted and pre-disposed tandem reaction sequences. For example, we have a long-standing interest in the study and synthesis of polyketide derived metabolites (the tridachiahydropyrones) isolated from marine molluscs. We have proposed and demonstrated, through experimentation, a complex biosynthetic scheme to explain the origins of these interesting compounds. Using our biomimetic photochemical approach, we have been able to synthesise and investigate the biological activities of these precious molecules. Employing complex biophysical techniques we have provided convincing evidence that these metabolites function as membrane bound sunscreens with anti-lipid peroxidation activity.
Chemical biology demonstrates how chemistry can be applied to solve biological problems, and with expertise in both Click and Biomimetic chemistry, we are ideally placed to exploit our skills in chemical biology applications. In collaboration with Prof Neil Oldham, we have developed a new protein foot-printing approach for application in the study of protein-protein, and protein-drug interactions. A photo-chemically activated molecular Click probe, that when irradiated, inserts into given regions of the target proteins. Mass spectroscopy techniques are then used to pinpoint patches of ligand-protein surface binding. What makes our approach unique is the flexibility of the probe design, which allows us to tune them to focus on certain areas of the protein. We have demonstrated the feasibility of our method for in a proof of principle study in several systems, and are currently developing the method for wider application. We are particularly keen to develop collaborations where we can utilise our molecular based methodology as a supporting technology for biology (See publications: Nat.Chem. Bio., 2017; Nat. Commun., 2016).