Evidence map›Paper›PMID 36933698›Full record

ArticleSLAS discovery : advancing life sciences R & D2023

A novel fluorogenic reporter substrate for 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCγ2): Application to high-throughput screening for activators to treat Alzheimer's disease.

Ramya Visvanathan, Tadanobu Utsuki, Daniel E Beck, Emma Lendy, Kuai-Lin Sun, Yinghui Liu, Kirk W Hering, Andrew Mesecar, Zhong-Yin Zhang, Karson S Putt

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in SLAS discovery : advancing life sciences R & D, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.5field-weighted citation impact, top 34% of its field
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

2 citing papers in PubMed, 3 citations in OpenAlex.

  1. Article
  2. Article
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

10 authors at 2 institutions in 1 country.

Ramya VisvanathanInstitute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; IUSM-Purdue TREAT-AD Center, West Lafayette IN 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Tadanobu UtsukiInstitute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; IUSM-Purdue TREAT-AD Center, West Lafayette IN 47907, USA.
Daniel E BeckInstitute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; IUSM-Purdue TREAT-AD Center, West Lafayette IN 47907, USA.
Emma LendyIUSM-Purdue TREAT-AD Center, West Lafayette IN 47907, USA; Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
Kuai-Lin SunCayman Chemical Company, 1180 East Ellsworth Road, Ann Arbor, MI 48108, USA.
Yinghui LiuCayman Chemical Company, 1180 East Ellsworth Road, Ann Arbor, MI 48108, USA.
Kirk W HeringCayman Chemical Company, 1180 East Ellsworth Road, Ann Arbor, MI 48108, USA.
Andrew MesecarIUSM-Purdue TREAT-AD Center, West Lafayette IN 47907, USA; Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
Zhong-Yin ZhangInstitute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; IUSM-Purdue TREAT-AD Center, West Lafayette IN 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Karson S PuttInstitute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; IUSM-Purdue TREAT-AD Center, West Lafayette IN 47907, USA. Electronic address: puttk@purdue.edu.
Purdue University West Lafayette · USCayman Chemical (United States) · US

Funding

Structural Biology CoreU54AG065181 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI Alan D. Palkowitz · 2019 to 2026
$61.3M
Structure/Function of Protein Tyrosine PhosphatasesR01CA069202 · NCI · YESHIVA UNIVERSITY · PI Zhong-Yin Zhang · 1996 to 2026
$7.3M
NCI NIH HHS R01 CA069202NIA NIH HHS U54 AG065181
6 · The paper itself

Abstract

A rare coding variant in PLCγ2 (P522R) expressed in microglia induces a mild activation of enzymatic activity when compared to wild-type. This mutation is reported to be protective against the cognitive decline associated with late-onset Alzheimer's disease (LOAD) and therefore, activation of wild-type PLCγ2 has been suggested as a potential therapeutic target for the prevention and treatment of LOAD. Additionally, PLCγ2 has been associated with other diseases such as cancer and some autoimmune disorders where mutations with much greater increases in PLCγ2 activity have been identified. Here, pharmacological inhibition may provide a therapeutic effect. In order to facilitate our investigation of the activity of PLCγ2, we developed an optimized fluorogenic substrate to monitor enzymatic activity in aqueous solution. This was accomplished by first exploring the spectral properties of various "turn-on" fluorophores. The most promising turn-on fluorophore was incorporated into a water-soluble PLCγ2 reporter substrate, which we named C8CF3-coumarin. The ability of PLCγ2 to enzymatically process C8CF3-coumarin was confirmed, and the kinetics of the reaction were determined. Reaction conditions were optimized to identify small molecule activators, and a pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC

Indexed as

Alzheimer DiseaseCoumarinsFluorescent DyesHigh-Throughput Screening AssaysHumansPhospholipase C gammaCoumarinsFluorescent DyesPhospholipase C gammaAlzheimer's diseaseC8CF3-coumarinHigh throughput screeningPhospholipase CPLCG2Turn-on fluorophore

Identifiers

PMID36933698
PMCPMC10251139
OpenAlexW4327560432

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.