Structure-guided design of a peripherally restricted chemogenetic system

被引：3

作者：

Kang, Hye Jin ^{[1
]}

Krumm, Brian E. ^{[2
]}

Tassou, Adrien ^{[3
]}

Geron, Matan ^{[3
]}

Diberto, Jeffrey F. ^{[2
,8
]}

Kapolka, Nicholas J. ^{[2
,8
]}

Gumpper, Ryan H. ^{[2
]}

Sakamoto, Kensuke ^{[2
]}

Kocak, D. Dewran ^{[2
]}

Olsen, Reid H. J. ^{[2
,7
]}

Huang, Xi-Ping ^{[2
,4
]}

Zhang, Shicheng ^{[2
]}

Huang, Karen L. ^{[3
]}

Zaidi, Saheem A. ^{[5
]}

Nguyen, MyV. T. ^{[5
]}

Jo, Min Jeong ^{[1
]}

Katritch, Vsevolod ^{[5
]}

Fay, Jonathan F. ^{[6
]}

Scherrer, Gregory ^{[3
]}

Roth, Bryan L. ^{[2
]}

机构：

[1] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul, South Korea

[2] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA

[3] Univ North Carolina Chapel Hill, UNC Neurosci Ctr, Dept Cell Biol & Physiol, Dept Pharmacol, Chapel Hill, NC 27599 USA

[4] Univ North Carolina Chapel Hill, Natl Inst Mental Hlth Psychoact Drug Screening Pro, Sch Med, Chapel Hill, NC USA

[5] Univ Southern Calif, Bridge Inst, Michelson Ctr Convergent Biosci,Dept Chem, Ctr New Technol Drug Discovery & Dev,Dept Quantita, Los Angeles, CA USA

[6] Univ Maryland, Sch Med, Biochem & Mol Biol, Baltimore, MD 21201 USA

[7] Exscientia, Cellular Pharmacol, Oxford, England

[8] EvE Bio LLC, Durham, NC 27703 USA

来源：

CELL | 2024年 / 187卷 / 26期

基金：

新加坡国家研究基金会;

关键词：

NICOTINIC-ACID RECEPTOR; FREE FATTY-ACIDS; PARTIAL AGONIST; PROTEIN; INTERROGATION; ACTIVATION; EXPRESSION; SOFTWARE; GPR109A; MK-0354;

D O I：

10.1016/j.cell.2024.11.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：7433 / 7449.e20

页数：38

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