MalDA, Accelerating Malaria Drug Discovery

Tuo Yang¹, Sabine Ottilie¹, Eva S Istvan², Karla P Godinez-Macias³, Amanda K Lukens⁴, Beatriz Baragaña⁵, Brice Campo⁶, Chris Walpole⁷, Jacquin C Niles⁸, Kelly Chibale⁹, Koen J Dechering¹⁰, Manuel Llinás¹¹, Marcus C S Lee¹², Nobutaka Kato¹³, Susan Wyllie⁵, Case W McNamara¹⁴, Francisco Javier Gamo¹⁵, Jeremy Burrows⁶, David A Fidock¹⁶, Daniel E Goldberg², Ian H Gilbert⁵, Dyann F Wirth⁴, Elizabeth A Winzeler¹⁷; Malaria Drug Accelerator Consortium

Affiliations

¹ Department of Pediatrics, School of Medicine, University of California, San Diego (UCSD), La Jolla, CA 92093, USA.
² Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO 63130, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63130, USA.
³ Bioinformatics and Systems Biology Graduate Program, University of California, San Diego (UCSD), La Jolla, CA 92093, USA.
⁴ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142, USA.
⁵ Wellcome Center for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
⁶ Medicines for Malaria Venture, 1215 Geneva 15, Switzerland.
⁷ Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
⁸ Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Building 56-341, 77 Massachusetts Avenue, Cambridge MA 02139-4307, USA.
⁹ Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
¹⁰ TropIQ Health Sciences, 6534 AT, Nijmegen, The Netherlands.
¹¹ Department of Biochemistry and Molecular Biology and Department of Chemistry, Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16082, USA.
¹² Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
¹³ Global Health Drug Discovery Institute, Zhongguancun Dongsheng International Science Park, 1 North Yongtaizhuang Road, Beijing 100192, China.
¹⁴ Calibr, a division of The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁵ Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
¹⁶ Department of Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹⁷ Department of Pediatrics, School of Medicine, University of California, San Diego (UCSD), La Jolla, CA 92093, USA. Electronic address: ewinzeler@health.ucsd.edu.

PMID: 33648890
PMCID: PMC8261838
DOI: 10.1016/j.pt.2021.01.009

Review

MalDA, Accelerating Malaria Drug Discovery

Tuo Yang et al. Trends Parasitol. 2021 Jun.

. 2021 Jun;37(6):493-507.

doi: 10.1016/j.pt.2021.01.009. Epub 2021 Feb 26.

Authors

Affiliations

¹ Department of Pediatrics, School of Medicine, University of California, San Diego (UCSD), La Jolla, CA 92093, USA.
² Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO 63130, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63130, USA.
³ Bioinformatics and Systems Biology Graduate Program, University of California, San Diego (UCSD), La Jolla, CA 92093, USA.
⁴ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142, USA.
⁵ Wellcome Center for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
⁶ Medicines for Malaria Venture, 1215 Geneva 15, Switzerland.
⁷ Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
⁸ Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Building 56-341, 77 Massachusetts Avenue, Cambridge MA 02139-4307, USA.
⁹ Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
¹⁰ TropIQ Health Sciences, 6534 AT, Nijmegen, The Netherlands.
¹¹ Department of Biochemistry and Molecular Biology and Department of Chemistry, Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16082, USA.
¹² Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
¹³ Global Health Drug Discovery Institute, Zhongguancun Dongsheng International Science Park, 1 North Yongtaizhuang Road, Beijing 100192, China.
¹⁴ Calibr, a division of The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁵ Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
¹⁶ Department of Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹⁷ Department of Pediatrics, School of Medicine, University of California, San Diego (UCSD), La Jolla, CA 92093, USA. Electronic address: ewinzeler@health.ucsd.edu.

PMID: 33648890
PMCID: PMC8261838
DOI: 10.1016/j.pt.2021.01.009

Abstract

The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific laboratories. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addition, it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclinical development and subsequent clinical testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chemically and biologically validated targets, as well as future scientific directions.

Keywords: MalDA; Plasmodium falciparum; drug resistance; malaria; target-based drug discovery.

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Conflict of interest statement

Declaration of Interests K.J.D. holds stock in TropIQ Health Sciences. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Figure 1.. Overview of MalDA (Malaria Drug Accelerator).**
MalDA is a consortium of 15 scientific laboratories (B), working in the earliest stages of drug discovery. By collaborating and sharing compounds and resources, MalDA can achieve milestones quickly and efficiently (A). Abbreviations: BMGF, Bill and Melinda Gates Foundation; Calibr, California Institute for Biomedical Research; CUIMC, Columbia University Irving Medical Center; DDU, Drug discovery unit – University of Dundee; GHDDI, Global Health Drug Discovery Institute; GSK, GlaxoSmithKline; Harvard Chan, Harvard T.H. Chan School of Public Health; HTS, High-throughput screening; IVIEWGA, *in vitro* evolution and whole-genome analysis; MIT, Massachusetts Institute of Technology; MMV, Medicines for Malaria Venture; Penn State, The Pennsylvania State University; SDDC, Structure-guided Drug Discovery Coalition; TropIQ, TropIQ Health Sciences; UCSD, University of California San Diego; UCT, University of Cape Town; WGS, Whole-genome sequencing; WUSTL, Washington University in St Louis.

**Figure 2.. Overview of MalDA (Malaria Drug Accelerator) Pipeline for the Discovery of Novel Antimalarials.**
Phenotypic drug discovery includes screening compound libraries against blood- and liver-stage *Plasmodium* parasites (A). The first steps to identify the target of an active hit compound utilize *in vitro* evolution and whole-genome analysis (IVIEWGA), metabolomics, chemoproteomics, and chemoinformatics approaches, followed by target validation via genetic and chemical approaches (B). Genetic validation uses clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) to reconstitute the resistant alleles found in IVIEWGA experiments. In conditional knockdown (KD) experiments, parasites are subjected to compound challenges to probe for dose–response changes (chemical validation and vulnerability assessment) and confirm compound hypersensitivity through diminished target expression (B). Validated targets can be rescreened for additional specific inhibitors using, for example, DNA-encoded libraries or target-specific libraries (C). Active compounds from phenotypic screening assays can also be directed to hit-to-lead development to be optimized for enhanced pharmaceutical properties. The resulting lead compounds are further examined in the *in vitro* assays against different malaria parasite developmental cycles and *in vivo* efficacy and pharmacokinetic/pharmacodynamics (PK/PD) studies in *Plasmodium falciparum* severe combined immunodeficiency (SCID) or NSG mouse models (D).

**Figure I.. *Plasmodium* Life Cycle and Points for Intervention.**
Abbreviation: TCP, target candidate profile.

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References

1. World Health Organization (2020) World Malaria Report 2020: 20 Years of Global Progress and Challenges, WHO
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MalDA, Accelerating Malaria Drug Discovery

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MalDA, Accelerating Malaria Drug Discovery

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Conflict of interest statement

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