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Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex

Overview of attention for article published in Malaria Journal, August 2015
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About this Attention Score

  • Above-average Attention Score compared to outputs of the same age (62nd percentile)
  • Average Attention Score compared to outputs of the same age and source

Mentioned by

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4 tweeters
facebook
1 Facebook page

Citations

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9 Dimensions

Readers on

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54 Mendeley
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Title
Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex
Published in
Malaria Journal, August 2015
DOI 10.1186/s12936-015-0834-9
Pubmed ID
Authors

Sondra Maureen Nemetski, Timothy J Cardozo, Gundula Bosch, Ryan Weltzer, Kevin O’Malley, Ijeoma Ejigiri, Kota Arun Kumar, Carlos A Buscaglia, Victor Nussenzweig, Photini Sinnis, Jelena Levitskaya, Jürgen Bosch

Abstract

Emerging resistance of the malaria parasite Plasmodium to current therapies underscores the critical importance of exploring novel strategies for disease eradication. Plasmodium species are obligate intracellular protozoan parasites. They rely on an unusual form of substrate-dependent motility for their migration on and across host-cell membranes and for host cell invasion. This peculiar motility mechanism is driven by the 'glideosome', an actin-myosin associated, macromolecular complex anchored to the inner membrane complex of the parasite. Myosin A, actin, aldolase, and thrombospondin-related anonymous protein (TRAP) constitute the molecular core of the glideosome in the sporozoite, the mosquito stage that brings the infection into mammals. Virtual library screening of a large compound library against the PfAldolase-TRAP complex was used to identify candidate compounds that stabilize and prevent the disassembly of the glideosome. The mechanism of these compounds was confirmed by biochemical, biophysical and parasitological methods. A novel inhibitory effect on the parasite was achieved by stabilizing a protein-protein interaction within the glideosome components. Compound 24 disrupts the gliding and invasive capabilities of Plasmodium parasites in in vitro parasite assays. A high-resolution, ternary X-ray crystal structure of PfAldolase-TRAP in complex with compound 24 confirms the mode of interaction and serves as a platform for future ligand optimization. This proof-of-concept study presents a novel approach to anti-malarial drug discovery and design. By strengthening a protein-protein interaction within the parasite, an avenue towards inhibiting a previously "undruggable" target is revealed and the motility motor responsible for successful invasion of host cells is rendered inactive. This study provides new insights into the malaria parasite cell invasion machinery and convincingly demonstrates that liver cell invasion is dramatically reduced by 95 % in the presence of the small molecule stabilizer compound 24.

Twitter Demographics

The data shown below were collected from the profiles of 4 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 54 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 2 4%
Unknown 52 96%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 13 24%
Student > Master 11 20%
Researcher 9 17%
Student > Bachelor 8 15%
Student > Postgraduate 5 9%
Other 4 7%
Unknown 4 7%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 14 26%
Agricultural and Biological Sciences 13 24%
Chemistry 11 20%
Medicine and Dentistry 4 7%
Pharmacology, Toxicology and Pharmaceutical Science 3 6%
Other 4 7%
Unknown 5 9%

Attention Score in Context

This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 03 September 2015.
All research outputs
#2,228,326
of 5,974,186 outputs
Outputs from Malaria Journal
#965
of 2,220 outputs
Outputs of similar age
#70,894
of 193,068 outputs
Outputs of similar age from Malaria Journal
#62
of 122 outputs
Altmetric has tracked 5,974,186 research outputs across all sources so far. This one has received more attention than most of these and is in the 62nd percentile.
So far Altmetric has tracked 2,220 research outputs from this source. They receive a mean Attention Score of 4.4. This one has gotten more attention than average, scoring higher than 54% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 193,068 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 62% of its contemporaries.
We're also able to compare this research output to 122 others from the same source and published within six weeks on either side of this one. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.