Structure-guided design of a peripherally restricted chemogenetic system

Hye Jin Kang; Brian E Krumm; Adrien Tassou; Matan Geron; Jeffrey F DiBerto; Nicholas J Kapolka; Ryan H Gumpper; Kensuke Sakamoto; D Dewran Kocak; Reid H J Olsen; Xi-Ping Huang; Shicheng Zhang; Karen L Huang; Saheem A Zaidi; MyV T Nguyen; Min Jeong Jo; Vsevolod Katritch; Jonathan F Fay; Grégory Scherrer; Bryan L Roth

doi:10.1016/j.cell.2024.11.001

Structure-guided design of a peripherally restricted chemogenetic system

Cell. 2024 Nov 25:S0092-8674(24)01275-3. doi: 10.1016/j.cell.2024.11.001. Online ahead of print.

Authors

Hye Jin Kang¹, Brian E Krumm², Adrien Tassou³, Matan Geron³, Jeffrey F DiBerto², Nicholas J Kapolka², Ryan H Gumpper², Kensuke Sakamoto², D Dewran Kocak², Reid H J Olsen², Xi-Ping Huang⁴, Shicheng Zhang², Karen L Huang³, Saheem A Zaidi⁵, MyV T Nguyen⁵, Min Jeong Jo¹, Vsevolod Katritch⁵, Jonathan F Fay⁶, Grégory Scherrer⁷, Bryan L Roth⁸

Affiliations

¹ Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
² Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Quantitative and Computational Biology, Department of Chemistry, Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
⁶ Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, Baltimore, MD 21201, USA.
⁷ Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
⁸ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected].

PMID: 39631393
DOI: 10.1016/j.cell.2024.11.001

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.

Keywords: GPCR; chemogenetics; peripheral nervous system.