Evidence map›Paper›PMID 29713966›Full record

ArticleJournal of the American Society for Mass Spectrometry2019

Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer's Disease.

Matthew A Downey, Maxwell J Giammona, Christian A Lang, Steven K Buratto, Ambuj Singh, Michael T Bowers

Erratum issuedAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of the American Society for Mass Spectrometry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. Article
  2. Biophysical characteristics of lipid-induced Aβ oligomers correlate to distinctive phenotypes in transgenic mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021
    Article
  3. Review
  4. Article
  5. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

6 authors.

Matthew A DowneyDepartment of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
Maxwell J GiammonaDepartment of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
Christian A LangAcelot, Inc., 5385 Hollister Ave, Suite 111, Santa Barbara, CA, 93111, USA.
Steven K BurattoDepartment of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
Ambuj SinghAcelot, Inc., 5385 Hollister Ave, Suite 111, Santa Barbara, CA, 93111, USA.
Michael T BowersDepartment of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA. bowers@chem.ucsb.edu.

Funding

Amyloid Beta-Protein: Wild Type and Familial Mutant Assembly and InhibitionR01AG047116 · NIA · UNIVERSITY OF CALIFORNIA SANTA BARBARA · PI BOWERS, MICHAEL THOMAS · 2013 to 2016
$1.8M
Army Research Laboratory DAAD 19-03-1-0121Army Research Laboratory W911NF-09-1-0280National Institute on Aging 1R01AG047116NIA NIH HHS R01 AG047116
6 · The paper itself

Abstract

Alzheimer's disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid β-protein, particularly the 42-residue alloform (Aβ42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aβ inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule's efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Aβ42 dodecamer at both high (1:10) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Aβ42, destabilizes preformed fibrils, and reverses Aβ42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development. Graphical Abstract.

Indexed as

Drug DesignModels, MolecularAlzheimer DiseaseAmyloid beta-PeptidesBlood-Brain BarrierDrug Evaluation, PreclinicalHumansIon Mobility SpectrometryMachine LearningMicroscopy, Atomic ForceNitrilesPeptide FragmentsPyrrolidinesAmyloid beta-Peptidesamyloid beta-protein (1-42)NitrilesPeptide FragmentsPyrrolidinesAggregationAlzheimer’s diseaseAmyloid-β proteinAtomic force microscopyAβ42InhibitionIon mobility mass spectrometryJoint pharmacophore space

Identifiers

PMID29713966
PMCPMC6258352

What OpenQuestion holds

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Registered trials

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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.