Chemical mapping of the PPIase interactome in C. elegans - development of a systems biology toolbox

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Caenorhabditis elegans (C. elegans) is a free living round worm comprising only 959 cells. Its genome produces 19,000 proteins (compared with some 25,000 from the human genome). We will introduce chemicals into the worms and look to see how they respond, particularly in terms of changes in their proteins. Small molecules which might be hormones, drugs or toxins can have profound effects on biological systems. Changes are usually caused by the small molecules (ligands) binding directly to a particular 'target protein' and stopping it from performing its normal function. These types of molecules are known as inhibitors. Currently we have a very poor understanding of the 'knock-on' effects in the cell when a given protein is bound to a ligand. We want to design molecules that bind to particular families of proteins in C.elegans and then modify their behaviour. We will monitor the effect of the chemical on the whole worm and identify which of the other proteins are affected. In this project we will only look at one family of proteins, the immunophilins, for which we have considerable background knowledge. Over 20 different proteins belong to this family. We know that they can act as enzymes and also help protein folding. We have synthesised new classes of molecules that inhibit these immunophilins and also show biological activity in the C.elegans. We have already put fluorescent-labels on some of these inhibitor molecules so that we see (using an optical microscope) where the molecules are taken up by the worm. We will see how proteins in worm change when they are exposed to these inhibitor ligands. By testing the many hundreds of different inhibitors that will be made in this project, we will identify molecules that have specific biological effects. Many of the proteins in C. elegans are similar to those in mammals, and so we will also learn about the effect of these chemicals in animal systems. Our data from worms could have a major impact on human and veterinary biology in areas like gene regulation, developmental biology, and drug discovery.