Our group uses chemogenetic techniques to investigate biological processes. These techniques are based on the use of small molecules to identify functional or regulatory pathways in biological systems. The interaction between a small molecule and a protein induces a phenotype. Once characterized, it allows to associate a protein to a molecular event. Chemogenomics is comparable to genetics except that the gene is not modified. The advantage of this technique is that the function of a protein is modified rather than the gene. The other advantages are reversibility and observation of the interaction in real-time. Indeed, the modification of a phenotype occurs only after addition of the molecule and can be interrupted after its withdrawal from the medium.
Chemogenomics is used in two different ways : classical chemogenomics and reverse chemogenomics. In classical chemogenomics, a particular phenotype (e.g iodine transport into thyrocytes) is studied and small molecules interacting with this function are identified. Once the modulators have been identified, they will be used as tools to look for the protein responsible for the phenotype. The target can be identified following several methods. The most current approaches are chromatography and affinity photolabeling, screening of expression clones or of protein chips. Another less direct method is based on the comparison of results with the activity profiles of known bioactive compounds. One of the disadvantages of classical chemogenomics is the lack of specificity and the low affinity of the compounds for their targets. It is often necessary to verify the results by classical genetic methods (e.g. gene knockout, SiRNA…).
In reverse chemogenomics, one looks for small molecules that perturb the function of an enzyme in the context of an in vitro enzymatic test. Once the modulators have been identified, the phenotype induced by the molecule is analyzed in a test on cells or on whole organisms. This method allows us to identify or to confirm the role of the enzyme in the biological response.
Comparison of chemogenomic techniques
Whatever the method used, this technique involves a high throughput screen of a chemical library of several thousand molecules.