Evidence map›Paper›PMID 36542544›Full record

ArticleACS chemical neuroscience2023

Perphenazine-Macrocycle Conjugates Rapidly Sequester the Aβ42 Monomer and Prevent Formation of Toxic Oligomers and Amyloid.

Sarah R Ball, Julius S P Adamson, Michael A Sullivan, Manuela R Zimmermann, Victor Lo, Maximo Sanz-Hernandez, Xiaofan Jiang, Ann H Kwan, André D J McKenzie, Eryn L Werry and 6 more

Abstract read
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In one paragraph

Article in ACS chemical neuroscience, 2023. 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

16 authors.

Sarah R BallSchool of Medical Sciences, The University of Sydney, Sydney, New South Wales2006, Australia.
Julius S P AdamsonSchool of Chemistry, The University of Sydney, Sydney, New South Wales2006, Australia.
Michael A SullivanSchool of Medical Sciences, The University of Sydney, Sydney, New South Wales2006, Australia.
Manuela R ZimmermannCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.ORCID 0000-0002-3443-2050
Victor LoSchool of Medical Sciences, The University of Sydney, Sydney, New South Wales2006, Australia.
Maximo Sanz-HernandezDepartment of Life Sciences, Imperial College London, South KensingtonSW7 2AZ, U.K.
Xiaofan JiangSchool of Chemistry, The University of Sydney, Sydney, New South Wales2006, Australia.
Ann H KwanSchool of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales2006, Australia.
André D J McKenzieSchool of Chemistry, The University of Sydney, Sydney, New South Wales2006, Australia.ORCID 0000-0002-8012-4745
Eryn L WerrySchool of Chemistry, The University of Sydney, Sydney, New South Wales2006, Australia.
Tuomas P J KnowlesCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.ORCID 0000-0002-7879-0140
Michael KassiouSchool of Chemistry, The University of Sydney, Sydney, New South Wales2006, Australia.ORCID 0000-0002-6655-0529
Georg MeislCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.ORCID 0000-0002-6562-7715
Matthew H ToddSchool of Pharmacy, University College London, LondonWC1N 1AX, U.K.ORCID 0000-0001-7096-4751
Peter J RutledgeSchool of Chemistry, The University of Sydney, Sydney, New South Wales2006, Australia.ORCID 0000-0002-0767-5196
Margaret SundeSchool of Medical Sciences, The University of Sydney, Sydney, New South Wales2006, Australia.ORCID 0000-0002-0150-3203

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aβ42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aβ42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aβ42 monomer into amorphous aggregates that are not cytotoxic. Rapid monomer sequestration by the compounds reduces fibril assembly, even in the presence of pre-formed fibrillar seeds. The compounds are therefore also able to disrupt monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers. The inhibitors have a modular design that is easily varied, aiding future exploration and use of these tools to probe the impact of distinct Aβ42 species populated during amyloid assembly.

Indexed as

Alzheimer DiseasePerphenazineAmyloidAmyloid beta-PeptidesAmyloidogenic ProteinsHumansPeptide FragmentsAmyloidAmyloid beta-Peptidesamyloid beta-protein (1-42)Amyloidogenic ProteinsPeptide FragmentsPerphenazineAlzheimer’s diseaseamyloidinhibitionkinetic analysismonomer sequestrationoligomers

Identifiers

PMID36542544
PMCPMC9818246

What OpenQuestion holds

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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 OpenQuestion graph.