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In vitro and in vivo anti-malarial activity of novel harmine-analog heat shock protein 90 inhibitors: a possible partner for artemisinin

Overview of attention for article published in Malaria Journal, December 2016
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2 tweeters

Citations

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23 Dimensions

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33 Mendeley
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Title
In vitro and in vivo anti-malarial activity of novel harmine-analog heat shock protein 90 inhibitors: a possible partner for artemisinin
Published in
Malaria Journal, December 2016
DOI 10.1186/s12936-016-1625-7
Pubmed ID
Authors

Abebe Genetu Bayih, Asongna Folefoc, Abu Naser Mohon, Scott Eagon, Marc Anderson, Dylan R. Pillai

Abstract

The emergence of artemisinin-resistant Plasmodium falciparum strains poses a serious challenge to the control of malaria. This necessitates the development of new anti-malarial drugs. Previous studies have shown that the natural beta-carboline alkaloid harmine is a promising anti-malarial agent targeting the P. falciparum heat-shock protein 90 (PfHsp90). The aim of this study was to test the anti-malarial activity of harmine analogues. Forty-two harmine analogues were synthesized and the binding of these analogues to P. falciparum heat shock protein 90 was investigated. The in vitro anti-malarial activity of two of the analogues, 17A and 21A, was evaluated using a 72-h growth inhibition assay. The in vivo anti-malarial activity was tested in Plasmodium berghei infection of BALB/c mice. The potential of 21A for a combination treatment with artemisinin was evaluated using in vivo combination study with dihydro-artemisinin in BALB/c mice. Cytotoxicity of the harmine analogues was tested in vitro using HepG2 and HeLa cell lines. 17A and 21A bound to PfHsp90 with average IC50 values of 12.2 ± 2.3 and 23.1 ± 8.8 µM, respectively. They also inhibited the P. falciparum W2 strain with average IC50 values of 4.2 ± 1.3 and 5.7 ± 1.7 µM, respectively. In vivo, three daily injections of P. berghei-infected BALB/c mice with 100 mg/kg of either 17A or 21A showed significant reduction in parasitaemia with a 51.5 and 56.1% reduction, respectively. Mice treated with 17A and 21A showed a median survival time of 11 and 14 days, respectively, while the vehicle control mice survived a median of only 8.5 days. A dose-ranging experiment with 21A showed that the compound has a dose-dependent anti-malarial effect. Furthermore, treatment of infected mice with a combination of 21A and dihydroartemisinin (DHA) showed a dramatic reduction in parasitaemia compared to treatment with DHA alone. A novel and non-toxic harmine analogue has been synthesized which binds to PfHsp90 protein, inhibits P. falciparum in vitro at micromolar concentration, reduces parasitaemia and prolongs survival of P. berghei-infected mice with an additive anti-malarial effect when combined with DHA.

Twitter Demographics

The data shown below were collected from the profiles of 2 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 33 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 33 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 6 18%
Student > Ph. D. Student 6 18%
Researcher 4 12%
Student > Master 3 9%
Student > Doctoral Student 2 6%
Other 2 6%
Unknown 10 30%
Readers by discipline Count As %
Pharmacology, Toxicology and Pharmaceutical Science 6 18%
Biochemistry, Genetics and Molecular Biology 4 12%
Chemistry 4 12%
Medicine and Dentistry 3 9%
Agricultural and Biological Sciences 3 9%
Other 0 0%
Unknown 13 39%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. 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 07 December 2016.
All research outputs
#12,618,285
of 19,153,137 outputs
Outputs from Malaria Journal
#4,000
of 5,057 outputs
Outputs of similar age
#237,633
of 407,656 outputs
Outputs of similar age from Malaria Journal
#428
of 561 outputs
Altmetric has tracked 19,153,137 research outputs across all sources so far. This one is in the 23rd percentile – i.e., 23% of other outputs scored the same or lower than it.
So far Altmetric has tracked 5,057 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.3. This one is in the 14th percentile – i.e., 14% of its peers scored the same or lower than it.
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 407,656 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 32nd percentile – i.e., 32% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 561 others from the same source and published within six weeks on either side of this one. This one is in the 18th percentile – i.e., 18% of its contemporaries scored the same or lower than it.