Ex vivo and In vitro antiplasmodial activities of approved drugs predicted to have antimalarial activities using chemogenomics and drug repositioning approach

Douglas O Ochora; Reagan M Mogire; Rael J Masai; Redemptah A Yeda; Edwin W Mwakio; Joseph G Amwoma; Dancan M Wakoli; Abiy Yenesew; Hoseah M Akala

doi:10.1016/j.heliyon.2023.e18863

Ex vivo and In vitro antiplasmodial activities of approved drugs predicted to have antimalarial activities using chemogenomics and drug repositioning approach

Heliyon. 2023 Aug 1;9(8):e18863. doi: 10.1016/j.heliyon.2023.e18863. eCollection 2023 Aug.

Authors

Douglas O Ochora^{1

2

3}, Reagan M Mogire⁴, Rael J Masai¹, Redemptah A Yeda³, Edwin W Mwakio³, Joseph G Amwoma⁵, Dancan M Wakoli⁶, Abiy Yenesew⁷, Hoseah M Akala³

Affiliations

¹ Department of Biological Sciences, School of Pure and Applied Sciences, Kisii University, P.O. Box 408-40200, Kisii, Kenya.
² DSI/NWU, Preclinical Drug Development Platform, Faculty of Health Sciences, North-West University, Private Bag X6001, 2520, Potchefstroom, South Africa.
³ United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, P.O. Box 54-40100, Kisumu, Kenya.
⁴ Kenya Medical Research Institute (KEMRI) - Kemri-Wellcome Trust Research Programme, P.O. Box 230-80108, Kilifi, Kenya.
⁵ Department of Biological Sciences, University of Embu P. O. Box 6-60100, Embu, Kenya.
⁶ Department of Biochemistry and Molecular Biology, Egerton University, P.O. Box 536-20115, Egerton-Njoro, Kenya.
⁷ Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya.

Abstract

High malaria mortality coupled with increased emergence of resistant multi-drug resistant strains of Plasmodium parasite, warrants the development of new and effective antimalarial drugs. However, drug design and discovery are costly and time-consuming with many active antimalarial compounds failing to get approved due to safety reasons. To address these challenges, the current study aimed at testing the antiplasmodial activities of approved drugs that were predicted using a target-similarity approach. This approach is based on the fact that if an approved drug used to treat another disease targets a protein similar to Plasmodium falciparum protein, then the drug will have a comparable effect on P. falciparum. In a previous study, in vitro antiplasmodial activities of 10 approved drugs was reported of the total 28 approved drugs. In this study, six out of 18 drugs that were previously not tested, namely epirubicin, irinotecan, venlafaxine, palbociclib, pelitinib, and PD153035 were tested for antiplasmodial activity. The drug susceptibility in vitro assays against five P. falciparum reference strains (D6, 3D7, W2, DD2, and F32 ART) and ex vivo assays against fresh clinical isolates were done using the malaria SYBR Green I assay. Standard antimalarial drugs were included as controls. Epirubicin and irinotecan showed excellent antiplasmodial ex vivo activity against field isolates with mean IC₅₀ values of 0.044 ± 0.033 μM and 0.085 ± 0.055 μM, respectively. Similar activity was observed against W2 strain where epirubicin had an IC₅₀ value of 0.004 ± 0.0009 μM, palbociclib 0.056 ± 0.006 μM, and pelinitib 0.057 ± 0.013 μM. For the DD2 strain, epirubicin, irinotecan and PD 153035 displayed potent antiplasmodial activity (IC₅₀ < 1 μM). Epirubicin and irinotecan showed potent antiplasmodial activities (IC₅₀ < 1 μM) against DD2, D6, 3D7, and F32 ART strains and field isolates. This shows the potential use of these drugs as antimalarials. All the tested drugs showed antiplasmodial activities with IC₅₀ values below 20 μM, which suggests that our target similarity-based strategy is successful at predicting antiplasmodial activity of compounds thereby circumventing challenges in antimalarial drug discovery.

Keywords: Antiplasmodial; Chemogenomics; Drug reportioning; Epirubicin; Ex vivo; Irinotecan; Plasmodium falciparum.