Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum, using a nano luciferase reporter read-out.
| Autor: | Dechering KJ; TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, The Netherlands., Timmerman M; Pivot Park Screening Centre, Oss, North Brabant, The Netherlands., Rensen K; Pivot Park Screening Centre, Oss, North Brabant, The Netherlands., Koolen KMJ; TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, The Netherlands., Honarnejad S; Pivot Park Screening Centre, Oss, North Brabant, The Netherlands., Vos MW; TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, The Netherlands., Huijs T; TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, The Netherlands., Henderson RWM; TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, The Netherlands., Chenu E; Medicines for Malaria Venture, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva 15, Switzerland., Laleu B; Medicines for Malaria Venture, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva 15, Switzerland., Montefiore BC; Optibrium, F5-6 Blenheim House, Cambridge Innovation Park, Denny End Road, Cambridge CB25 9PB, United Kingdom., Segall MD; Optibrium, F5-6 Blenheim House, Cambridge Innovation Park, Denny End Road, Cambridge CB25 9PB, United Kingdom., Mills JEJ; Sandexis Medicinal Chemistry Ltd, Innovation House, Discovery Park, Sandwich, CT13 9FF, United Kingdom., Guantai EM; Department of Pharmacy, Faculty of Health Sciences, University of Nairobi, 00202, Nairobi, Kenya., Duffy J; Medicines for Malaria Venture, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva 15, Switzerland., Duffey M; Medicines for Malaria Venture, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva 15, Switzerland. Electronic address: duffeym@mmv.org. |
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| Jazyk: | angličtina |
| Zdroj: | SLAS discovery : advancing life sciences R & D [SLAS Discov] 2022 Sep; Vol. 27 (6), pp. 337-348. Date of Electronic Publication: 2022 Jul 21. |
| DOI: | 10.1016/j.slasd.2022.07.002 |
| Abstrakt: | A central challenge of antimalarial therapy is the emergence of resistance to the components of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. Over the last decade, compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. However, the published screening data which provided much of the new chemical matter for malaria drug discovery projects have been extensively mined. Here we present a new screening and selection cascade for generation of hit compounds active against the blood stage of Plasmodium falciparum. In addition, we validate our approach by testing a library of 141,786 compounds not reported earlier as being tested against malaria. The Hit Generation Library 1 (HGL1) was designed to maximise the chemical diversity and novelty of compounds with physicochemical properties associated with potential for further development. A robust HTS cascade containing orthogonal efficacy and cytotoxicity assays, including a newly developed and validated nanoluciferase-based assay was used to profile the compounds. 75 compounds (Screening Active hit rate of 0.05%) were identified meeting our stringent selection criteria of potency in drug sensitive (NF54) and drug resistant (Dd2) parasite strains (IC Competing Interests: Declaration of Conflicting Interests E.C., B.L., J.D. and M.D. are employees of one of the funders, Medicines for Malaria Venture (MMV). The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. (Copyright © 2022. Published by Elsevier Inc.) |
| Databáze: | MEDLINE |
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