Many critical processes within cells, including those that control whether a cell lives and divides or dies, are mediated by protein–protein interactions (PPIs). In certain disease states, such as cancer, these interactions can become defective in a way where disruption of the interaction has therapeutic benefit. Replacement of one of the protein partners, which often have α-helical secondary structure, with a small molecule is one method of disruption; however, the interface can often be large and shallow, making the design of competitive small molecules challenging. The saving grace is that the interaction energy is usually dominated by the interactions of a few amino acid residues, which protrude from one or more faces of the α-helical peptide. The design of α-helical mimetics that are non-peptidic in nature and that can replicate the positioning of these hotspot residues has been an active area of research. The host laboratory has recently developed a method to prepare chains of substituted carbon atoms with complete control of absolute and relative configuration. Owing to the avoidance of syn-pentane interactions, the all-syn and alternating syn–anti contiguously substituted chains fold into well-defined helical and linear conformations. The positioning of the substituents could uniquely replicate a pattern of hotspot residues that cover two or more faces of an α-helical peptide. This project will explore this possibility through the design, preparation and testing of mimetics that target the Mcl-1/Noxa-B PPI, which controls apoptosis and has leucine, arginine, isoleucine, aspartic acid, and valine at positions 11, 12, 14, 16 and 18 as hotspot residues. The project merges cutting-edge synthetic organic chemistry, multiple forms of computation, including molecular mechanics, density functional theory, and molecular dynamics, NMR spectroscopy, and medicinal chemistry.

Brains are like orchestras. Both are subdivided into numerous, specialized sections with individual roles, yet the activity of all sections must be coordinated in order for the whole to function properly. Musicians in an orchestra keep time by following the lead of their conductor; by analogy, how do neurons of different brain regions coordinate their activity during the complex repertoire of behaviour? Electrophysiology allows us to record the electrical impulses through which neurons communicate. We find that many groups of neurons, like the sections of an orchestra, show rhythmic activity. Rhythms in connected neural networks are coordinated with one another, but only during behaviour that requires communication between the brain regions that contain them. Thus rhythmic activity can act as the brain?s conductor, allowing different groups of neurons to communicate with one another at different times. This study will use recordings from three brain regions involved in learning and memory and decision-making to see how they interact during behaviour. All three of the regions in question show signs of damage in schizophrenic patients. We suspect that the brain behaves like a ?cacophonous orchestra? during schizophrenia: a breakdown of coordinated timing leads to cognitive and behavioural abnormalities because different brain regions do not keep time with one another. We can model schizophrenia in rats and mice. For example, if we give animals drugs like ketamine (?Special K?), they develop behavioural problems like those in psychotic patients. By recording from the neurons of these animals, we can characterize the breakdown in coordinated neural activity that accompanies their breakdown in behaviour. Then, by comparing electrophysiology from these animal models with electrophysiology from the clinic (the impulses of human neurons can be recorded through the scalp as EEG, or ?brain waves?), we can begin to understand what goes wrong in the schizophrenic brain and, most importantly, begin to test therapies that will eventually put it right.

The CDT PhD Project will start in the second year of the programme, Sept 2020