Chemogenetics a robust approach to pharmacology and gene therapy

Modern developments in organic chemistry, molecular biology, virology, and genetics have opened new, exciting possibilities to better understand physiology and to create innovative, robust therapeutics. One such possibility is the burgeoning field of chemogenetics, a sub-field of chemical genetics that encompasses engineering macromolecules (particularly proteins) to modify how they interact with endogenous and exogenous ligands (particularly small molecules). Early efforts in chemogenetics were focused on parsing the function of a specific enzyme within a closely-related family by creating orthogonal enzyme-ligand pairs (e.g. kinases paired with antagonists). This powerful concept quickly expanded into engineered G-protein-coupled receptors (e.g. DREADDs/RASSL), and more recently into engineered ligand-gated ion channels (eLGIC). The modifications to the receptor focused on eliminating their activation by endogenous ligands, while preserving or enhancing their interaction with pharmacological agents (e.g. small molecule agonist). Creation of such an engineered receptor and delivering it selectively to specific cell types opens new possibilities of accurately and precisely controlling cellular activity. Control of this activity then increases our understanding of the cells function in normal physiology, while also creating the possibility of using it as a therapeutic to address pathophysiology. The DREADDs/RASSL and eLGIC approaches have been particularly impactful in neurosciences but have applications in multiple fields. In this work we introduce the history of the chemogenetic approach, review the seminal work with DREADDs/RASSLs and eLGIC, highlight the breadth of applications, and discuss the strengths and weaknesses associated with this technology, especially in the context of its development into a therapeutic.