At the Crossroads of Chemistry and Cell Biology: Inhibiting Membrane Traffic by Small Molecules

Intracellular membrane traffic regulates cell physiology at multiple levels ranging from cell growth and development to the function of the nervous and immune systems. Multiple endocytic routes are used by distinct cargoes including ligands bound to their receptors but also viruses and pathogens to gain access to the cell interior. Within the endosomal system, proteins and lipids are sorted for degradation or recycling allowing cells to dynamically respond to environmental signals and to regulate cell shape and morphology. Some receptors or toxins are sorted along the retrograde pathway from endosomes to the Golgi complex, where they intersect with secretory cargo destined for exocytosis. Genetic manipulations of these pathways frequently cause problems with regard to data interpretation as the resulting phenotypes may be indirect consequences resulting from perturbation of multiple steps or trafficking routes. Hence, novel approaches are needed to acutely and reversibly perturb intracellular membrane traffic, e.g., by small molecule inhibitors. Such drugs may also be pharmacologically important as they offer new avenues to fight human diseases. Here, we provide an overview of the small molecules available to interfere with intracellular membrane traffic and outline strategies for future research.