Designer Drugs for Designer Receptors: Unlocking the Translational Potential of Chemogenetics

Abstract

Chemogenetic techniques allow selective manipulation of neurons by activating engineered actuator proteins with otherwise inert effector molecules. A recent study (Magnus et al. Science 2019;364:eaav5282) describes the coevolution of highly potent actuator-effector pairs based on a clinically approved antismoking drug. These tools allow selective excitation or inhibition of neurons in the living brain with high specificity and no detectable side-effects.

Keywords: chemogenetics; drug design; gene therapy; neuromodulation.

Figure 1. A novel, highly selective and ultra-sensitive chemogenetic toolkit for manipulation of neuronal activity.

(A) Pharmacologically Selective Actuator Molecules (PSAMs) are chimera consisting of a ligand binding domain (LBD) from the α7-nicotinic acetylcholine receptor and an ion pore domain (IPD) of the glycine receptor (GlyR, anion-conducting) or the serotonin receptor (5HT, cation-conducting). (B) The acetylcholine binding pocket of the α7-nAChR-LBD (symbolizing the lock) is mutated to become selective for the Pharmacologically Selective Effector Molecule (PSAM) Varenicline, a clinically approved anti-smoking drug. (C) Expression of PSAM⁴-GlyR and PSAM⁴-5HT in defined neuronal populations allows selective down- or upregulation of neuronal activity with nanomolar concentrations of Varenicline and ultrapotent PSEMs (uPSEMs). (D) uPSEMs (symbolizing the keys to fit the binding pocket of the LBD) are derived from Varenicline and optimized to fit the PSAM⁴ binding pocket with higher specificity than Varenicline.