Our research is centred on developing chemical tools to understand and inhibit therapeutically significant protein-protein interactions. This work encompasses aspects of chemical biology, synthetic organic chemistry, peptide and protein chemistry, chemical proteomics and medicinal chemistry. The group is highly multidisciplinary in nature and we work in collaboration with groups at Imperial within Natural Science and Medicine and with other labs across the UK.
Design and Synthesis of Novel Helix-Mimetic Scaffolds
Compared to more traditional drug targets such as enzyme-substrate interactions, PPIs occur over large and often topologically challenging binding interfaces which has led to them being long considered ‘undruggable’. However, the critical observation that PPIs are driven by a small number of key interacting ‘hot-spot’ residues, can provide a powerful starting point for inhibitor design.α-Helices are by far the most abundant structural element found in proteins and analysis of multi-protein complexes has shown that this motif is present at the interaction interface of about two-thirds of PPIs. Helix mimetics are a unique class of PPI inhibitor since they present binding groups in approximately the same orientation as key amino acid residues in the helical component of a PPI.
Although such ‘proteomimetics’ have successfully targeted PPIs, to date they can target only a limited subset of surface exposed interfaces where interactions occur on just one face of the α-helix such that >40% of helix-mediated PPIs are currently undruggable. In order to address the lack of available multi-faced helix-mimetics, we have designed a series of novel scaffolds which position binding residues across two different faces. We are also working on expanding the range of chemical linkages between the monomer units which make up these helix-mimetic scaffolds.
Novel Stapled Peptides
Protein-protein interactions (PPIs) represent a large class of disease-relevant molecular targets where the binding interface is often challenging to target with a small molecule. In such cases, peptides sequences that mimic a key portion of the interacting protein interface provide an important alternative, but are subject to a key limitation: once separate from the whole protein a short peptide sequence no longer retains its (bioactive) conformation. A means to tackle this issue for helical peptides is through the use of a synthetic peptide ‘staple’ which locks the peptide sequence into a bioactive conformation. In collaboration with the Fuchter group at Imperial we are working on the development of unique photoaddressable ‘stapled’ peptides, which can be photoswitched between two conformational states enabling optical switching between an active peptide conformation (‘on’) and an inactive (‘off’) one. Light provides an unrivalled stimuli for such studies, offering the possibility of non-invasively manipulating light responsive molecules within cells.
Inhibiting a Myosin Motor Protein in Malaria Parasites
The disease malaria is one of the most prolific endemics worldwide with approximately 200 million recorded cases and half a million deaths in 2015. With the constant development of drug resistance by parasites an effective treatment remains elusive. Most cases originate from the parasite Plasmodium falciparum and the infection is critically dependant on the invasion of red blood cells. This invasion mechanism is controlled by a complex array of proteins. The motility complex features myosin A (MyoA) which is anchored into the membrane by myosin tail interacting protein (MTIP). The interaction is controlled by a helical region of MyoA which binds into a specific hydrophobic cleft within an MTIP dimer. This protein-protein interaction (PPI) has been shown to be essential for producing the motive force required for invasion and thus represents a viable drug target for this disease.
We are currently applying some of our novel multi-facial helix mimetic scaffolds to the inhibition of this PPI. This project is in collaboration with Ed Tate, Ernesto Cota and Jake Baum at Imperial and Tony Holder at the Francis Crick Institute.
Exploring PPIs in Bacteria
Targeting protein-protein interactions (PPIs) for therapeutic intervention has proved to be a promising strategy throughout many areas of biology. However, this approach has rarely been applied to bacterial PPIs. The failure of antibiotics in the clinic is one of the most pressing challenges facing modern society and there is an urgent need to identify novel infection and control strategies. Bacterial persistence has become increasingly recognised as a major mechanism by which bacteria stop growing and evade antibiotics during the treatment of infection, prolonging treatment times and providing a reservoir of bacteria that seeds recurrent infections. Toxin-antitoxin (TA) operons are ubiquitous within bacteria and, when expressed form a harmless toxin-antitoxin PPI. These PPIs are critically linked to bacterial persistence.
In collaboration with Sophie Helaine in the Faculty of Medicine we are working on targeting the toxin with peptide based inhibitors with the aim of reversing persistence rendering the bacteria more sensitive to antibiotics.
If you are interested in initiating a collaboration we would be happy to hear from you. Please contact Dr Anna Barnard.
We are grateful to the following organisations for financial support: