Evidence map›Paper›PMID 41337857›Full record

ArticleMolecular pharmacology2025

Introduction of a single carboxylic acid converts the cyclic oligomeric depsipeptide ent-verticilide from a ryanodine receptor 2 (RyR2) inhibitor to RyR2 activator.

Tri Q Do, Daniel J Blackwell, Abigail N Smith, Madelaine P Thorpe, Robyn T Rebbeck, Derek R Laver, Jeffrey N Johnston, Björn C Knollmann

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

8 authors.

Tri Q DoVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Daniel J BlackwellVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Abigail N SmithDepartment of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee.
Madelaine P ThorpeDepartment of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee.
Robyn T RebbeckDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota.
Derek R LaverVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Jeffrey N JohnstonDepartment of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee.
Björn C KnollmannVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: bjorn.knollmann@vanderbilt.edu.

Funding

Toward a Mechanism-Based Approach to Treating Cardiac ArrhythmiaR35HL144980 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI KNOLLMANN, BJORN C · 2019 to 2025
$7.1M
Development of Mirror-Image Natural Products as Antiarrhythmic TherapeuticsR01HL181098 · NHLBI · VANDERBILT UNIVERSITY · PI Jeffrey Nicholas Johnston · 2025 to 2026
$1.5M
NHLBI NIH HHS R01 HL181098NHLBI NIH HHS R35 HL144980
6 · The paper itself

Abstract

Cyclic oligomeric depsipeptides represent a distinct structural class of naturally occurring compounds known for their wide-ranging biological activities. We previously reported that the unnatural form of verticilide (ent-verticilide) inhibits cardiac ryanodine receptor 2 (RyR2) and exhibits antiarrhythmic effects in mice, but its mechanism of action on the RyR2 channel is not known. Here, we collected single-channel recordings in artificial lipid bilayers to elucidate the mechanism of RyR2 modulation by ent-verticilide and its polar side chain analog activert. ent-Verticilide reduced RyR2 activity by increasing the RyR2 mean closed time without changing the RyR2 mean open time, suggesting that ent-verticilide functions as a closed-channel stabilizer. ent-Verticilide exhibited partial inhibition on RyR2 single channels with an IC

Indexed as

Carboxylic AcidsDepsipeptidesRyanodine Receptor Calcium Release ChannelAnimalsHEK293 CellsHumansMiceCarboxylic AcidsDepsipeptidesRyanodine Receptor Calcium Release ChannelCalcium release deficiency syndromeCardiac arrhythmiaCatecholaminergic polymorphic ventricular tachycardiaCyclic oligomeric depsipeptidesRyanodine receptorStructure-activity relationship

Identifiers

PMID41337857
PMCPMC12799544

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
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.