Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Aug:22:81-87.
doi: 10.1016/j.ijpddr.2023.05.005. Epub 2023 Jun 8.

Stepwise in vitro screening of MMV pathogen box compounds against Plasmodium falciparum to identify potent antimalarial candidates

Haddijatou Mbye  1 , Fatoumata Bojang  2 , Fatou Kene Jaiteh  2 , Aminata Jawara  2 , Bekai Njie  2 , Simon Correa  2 , Umberto D'Alessandro  2 , Alfred Amambua-Ngwa  3
Affiliations

Stepwise in vitro screening of MMV pathogen box compounds against Plasmodium falciparum to identify potent antimalarial candidates

Haddijatou Mbye et al. Int J Parasitol Drugs Drug Resist. 2023 Aug.

Abstract

Development of resistance to deployed antimalarial drugs is inevitable and needs prompt and continuous discovery of novel candidate drugs. Therefore, the antimalarial activity of 125 compounds from the Medicine for Malaria Ventures (MMV) pathogen box was determined. Combining standard IC50 and normalised growth rate inhibition (GR50) analyses, we found 16 and 22 compounds had higher potencies than CQ respectively. Seven compounds with relatively high potencies (low GR50 and IC50) against P. falciparum 3D7 were further analysed. Three of these were tested on 10 natural P. falciparum isolates from The Gambia using our newly developed parasite survival rate assay (PSRA). According to the IC50, GR50 and PSRA analyses, compound MMV667494 was most potent and highly cytotoxic to parasites. MMV010576 was slow acting but more potent than dihydroartemisinin (DHA) 72 h after exposure. MMV634140 was potent against the laboratory-adapted 3D7 isolate, but 4 out of 10 natural Gambian isolates survived and replicated slowly despite 72 h of exposure to the compound, suggesting potential drug tolerance and risk of resistance development. These results emphasise the usefulness of in vitro testing as a starting point for drug discovery. Improved approaches to data analyses and the use of natural isolates will facilitate the prioritisation of compounds for further clinical development.

Keywords: Antimalarial drug susceptibility; Malaria; Medicine for Malaria Venture (MMV); Pathogen box; Plasmodium falciparum.

PubMed Disclaimer

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Log10 IC50 for 125 compounds and GR50 for 75 compounds from the MMV pathogen box against Plasmodium falciparum-3D7 laboratory isolate.
Fig. 2
Fig. 2
Growth corrected responses of P. falciparum 3D7 isolate to seven potent antimalarial compounds. a) Sigmoid non-linear fit curves for IC50 determination for each compound. The error bars represent standard deviations for 3 replicates of each drug concentration tested. The dotted line shows the concentration at which 50% of the parasite population was inhibited by the compound. b) Growth inhibition curves for GR50 determination of selected compounds represented by separate lines.
Fig. 3
Fig. 3
Individual responses of 10 parasite samples following exposure to LUM, DHA, MMV667494, MMV010576, MMV634140 and a no-drug control (DMSO) at 6, 24, 48 and 72 h. The responses are shown in percentage parasitaemia and the error bars represent standard deviations of 3 individual replicates.
Fig. 4
Fig. 4
Percentage re-invasion parasitaemia of 10 P. falciparum field isolates analysed against (a) LUM, (b) DHA, (c) MMV667494, (d) MMV634140, and (e) MMV010576 at 72 h post exposure. (f) Responses of 10 field isolates following 72 h exposure to drugs, test compounds and no-drug control (DMSO). The error bars represent standard deviations from 3 individual replicates.
figs1
figs1
See this image and copyright information in PMC

References

    1. Amambua-Ngwa A., Okebe J., Mbye H., Ceesay S., El-Fatouri F., Joof F., Nyang H., Janha R., Affara M., Ahmad A., Kolly O., Nwakanma D., D'Alessandro U. Sustained ex vivo susceptibility of Plasmodium falciparum to artemisinin derivatives but increasing tolerance to artemisinin combination therapy partner quinolines in the Gambia. Antimicrob. Agents Chemother. 2017;61(12) doi: 10.1128/AAC.00759-17. - DOI - PMC - PubMed
    1. Balikagala B., Fukuda N., Ikeda M., Katuro O.T., Tachibana S.-I., Yamauchi M., Opio W., Emoto S., Anywar D.A., Kimura E., Palacpac N.M.Q., Odongo-Aginya E.I., Ogwang M., Horii T., Mita T. Evidence of artemisinin-resistant malaria in Africa. N. Engl. J. Med. 2021;385(13):1163–1171. doi: 10.1056/NEJMOA2101746/SUPPL_FILE/NEJMOA2101746_DISCLOSURES.PDF. - DOI - PubMed
    1. Baragana B., Norcross N.R., Wilson C., Porzelle A., Hallyburton I., Grimaldi R., Osuna-Cabello M., Norval S., Riley J., Stojanovski L., Simeons F.R.C., Wyatt P.G., Delves M.J., Meister S., Duffy S., Avery V.M., Winzeler E.A., Sinden R.E., Wittlin S., Gilbert I.H. Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. J. Med. Chem. 2016;59(21):9672–9685. doi: 10.1021/ACS.JMEDCHEM.6B00723. - DOI - PMC - PubMed
    1. Blasco B., Leroy Di, Fidock D.A. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nature Medicine 2017 23:8. 2017;23(8):917–928. doi: 10.1038/nm.4381. - DOI - PMC - PubMed
    1. Bloland P.B. World Health Organization; 2001. Drug Resistance in Malaria.https://apps.who.int/iris/handle/10665/66847

Publication types