Evidence map›Paper›PMID 39631393›Full record

ArticleCell2024

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 and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed.

  1. Trial
  2. Targeting GCell reports. Medicine · 2026
    Article
  3. Article
  4. Article
  5. Article
  6. Review
  7. Structural Perspectives on Biased Allostery of GPCR Signaling.Handbook of experimental pharmacology · 2026
    Review
  8. Neuro-immune cross-talk in cancer.Nature reviews. Cancer · 2025
    Review
  9. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors.

Hye Jin KangDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
Brian E KrummDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Adrien TassouDepartment of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Matan GeronDepartment of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jeffrey F DiBertoDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nicholas J KapolkaDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Ryan H GumpperDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Kensuke SakamotoDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
D Dewran KocakDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Reid H J OlsenDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Xi-Ping HuangDepartment 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.
Shicheng ZhangDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Karen L HuangDepartment of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Saheem A ZaidiDepartment 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.
MyV T NguyenDepartment 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.
Min Jeong JoDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
Vsevolod KatritchDepartment 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.
Jonathan F FayBiochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, Baltimore, MD 21201, USA.
Grégory ScherrerDepartment 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: gregory_scherrer@med.unc.edu.
Bryan L RothDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: bryan_roth@med.unc.edu.

Funding

Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI HONG JIN KIM · 1985 to 2026
$201.5M
Illuminating the Druggable GPCR-omeU24DK116195 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ROTH, BRYAN L., SHOICHET, BRIAN K · 2017 to 2022
$14.3M
Molecular Details of Psychoactive Drug ActionsR01MH112205 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Bryan L. Roth, Brian K Shoichet · 2017 to 2026
$6.1M
Identification of cells and signaling mechanisms underlying opioid analgesia and side effectsR01DA044481 · NIDA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SCHERRER, GREGORY · 2017 to 2021
$1.8M
Computational approaches to discover ligands with new chemotypes and functional propertiesR35GM153437 · NIGMS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI VSEVOLOD KATRITCH · 2024 to 2026
$899k
NCI NIH HHS P30 CA016086NIDA NIH HHS R01 DA044481NIDDK NIH HHS U24 DK116195NIGMS NIH HHS R35 GM153437NIMH NIH HHS R01 MH112205
6 · The paper itself

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.

Indexed as

Cryoelectron MicroscopyGanglia, SpinalAction PotentialsAnimalsBlood-Brain BarrierDesigner DrugsHEK293 CellsHumansMaleMiceMice, Inbred C57BLNeuronsPainRatsDesigner DrugschemogeneticsGPCRperipheral nervous system

Identifiers

PMID39631393
PMCPMC12291529

What Socratic holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.