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  • Review Article
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Antimalarial drug discovery: efficacy models for compound screening

Nature Reviews Drug Discovery volume 3, pages 509–520 (2004)Cite this article

Key Points

  • Increased antimalarial drug discovery efforts are urgently needed. The goal must be to develop safe and affordable new drugs to counter the spread of malaria parasites resistant to existing agents. Here, we review different in vitro and in vivo screens for antimalarial drug discovery and recommend a streamlined process for evaluating new compounds on a critical path from drug discovery to development.

  • Malaria caused by Plasmodium falciparum remains one of the most important diseases of the developing world, killing 1–3 million people and causing disease in 300–500 million people each year. Malaria-endemic regions of the world are faced with an unprecedented situation in which the only affordable treatment options, historically based on the use of chloroquine or sulphadoxine-pyrimethamine, are rapidly losing therapeutic efficacy.

  • Ideally, new drugs for uncomplicated P. falciparum malaria must be efficacious against drug resistant strains, provide cure within a reasonable time (ideally three days or less) to ensure good compliance, be safe, be suitable for small children and pregnant women, have appropriate formulations for oral use, and above all be affordable. Drug discovery necessarily requires trade-offs among desired drug features, but for the treatment of malaria in the developing world, the provision of affordable, orally active treatments that are safe for children is, for practical purposes, mandatory.

  • In vitro screens for compound activity are performed with P. falciparum strains of differing drug-susceptibility profiles that can be readily cultured in human erythrocytes. The most common screen involves measuring the uptake of 3H-hypoxanthine (which is taken up by the parasite for purine salvage and DNA synthesis) during a 48–72 hour period. This enables a determination of the level of P. falciparum growth inhibition as a function of the concentration of the test compound.

  • In vivo evaluation of antimalarial compounds typically begins with the use of rodent malaria parasites, either P. berghei, P. yoelii, P. chabaudi or P. vinckei. P. berghei is the most commonly used model. The most widely used initial screen is a four-day suppressive test, where the efficacy of four daily doses of compounds is measured by comparison of blood parasitaemia (on day four after infection) and mouse survival time in treated and untreated mice. Active compounds can be progressed through several secondary tests.

  • This review also provides an example of a critical path for an antimalarial drug discovery effort, lists targets currently being pursued, summarizes ongoing drug discovery and developments efforts and provides online links to informative websites.

Abstract

Increased efforts in antimalarial drug discovery are urgently needed. The goal must be to develop safe and affordable new drugs to counter the spread of malaria parasites that are resistant to existing agents. Drug efficacy, pharmacology and toxicity are important parameters in the selection of compounds for development, yet little attempt has been made to review and standardize antimalarial drug-efficacy screens. Here, we suggest different in vitro and in vivo screens for antimalarial drug discovery and recommend a streamlined process for evaluating new compounds on the path from drug discovery to development.

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Figure 1: The global distribution of malaria, showing areas where Plasmodium falciparum resistance to the most commonly used antimalarial drugs, chloroquine and sulphadoxine-pyrimethamine, has been documented.
Figure 2: Example of a critical path for antimalarial drug discovery.
Figure 3: Representation of an intra-erythrocytic Plasmodium falciparum trophozoite, highlighting key parasite intracellular compartments and the site of action of some of the major classes of antimalarial drugs.
Figure 4: Flow chart of one scenario for in vivo screening for antimalarial activity in rodent malaria models.
Figure 5: Crystal structure of Plasmodium falciparum enoyl-ACP reductase (PfENR) complexed with NAD+ cofactor and the inhibitor triclosan.

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Acknowledgements

The authors wish to thank the MMV staff for organizing the antimalarial drug screening meeting that prompted the writing of this article. The contribution of all attendees at that meeting (F. Buckner, D. Gargallo, W. Milhous, H. Matile, M. Bendig, Kevin Bauer, S. Kamchonwongpaisan, M.-A. Mouries, L. Riopel and C. Craft) who were not authors on this review is appreciated. J. Sacchettini and M. Kuo are gratefully acknowledged for contributing Figure 5.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    David A. Fidock

  2. Department of Medicine, Box 0811, University of California, San Francisco, 94143, California, USA

    Philip J. Rosenthal

  3. Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    Simon L. Croft

  4. Department of Medical Parasitology and Infection Biology, Parasite Chemotherapy, Swiss Tropical Institute, Basel, CH-4002, Switzerland

    Reto Brun

  5. Medicines for Malaria Venture, PO Box 1826, 1215 Geneva 15, Switzerland

    Solomon Nwaka

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  1. David A. Fidock
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  2. Philip J. Rosenthal
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  3. Simon L. Croft
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Correspondence to David A. Fidock.

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FURTHER INFORMATION

Antimalarial drug discovery: efficacy models for compound screening

Malaria Foundation International

Malaria Research and Reference Reagent Resource Center

Medicines for Malaria Venture

Plasmo DB

World Health Organization malaria page

Glossary

APICOMPLEXA

Lower eukaryotic, obligate intracellular parasites characterized by the presence of apical organelles involved in host cell invasion. Includes parasitic protozoa responsible for malaria (Plasmodium), toxoplasmosis (Toxoplasma), babesiosis (Babesia) and coccidiosis (Eimeria).

GAMETOCYTES

The sexual haploid stages produced in the blood that are infectious for the mosquito vector. Once inside the mosquito midgut, gametocytes transform into male or female gametes that can undergo fusion, genetic recombination and meiosis.

SPOROZOITES

The haploid parasite forms that reside in the mosquito salivary glands and that are infectious for the human host, where they rapidly invade hepatocytes and transform into liver stage parasites.

EFFICACY

A quantitative index of drug action, in this case related to suppression of malarial infection either in vitro or in vivo.

ANTIFOLATES

Drugs that target the folate biosynthesis pathway. Antimalarial antifolate drugs target dihydrofolate reductase or dihydropteroate synthase.

INTERMITTENT PREVENTIVE TREATMENT

Entails the administration of full therapeutic doses of a drug at defined intervals. Envisaged to confer a degree of sustained prophylactic protection in the most vulnerable populations, that is, young children and pregnant women.

CHEMOPROPHYLAXIS

Drug treatment designed to prevent future occurrences of disease.

POTENCY

An expression of the activity of a compound, in terms of the concentration required to produce a desired effect (for example, 50% inhibition of parasite growth).

ENDEMICITY

An expression of the seasonality and degree of transmission in a malaria-afflicted region.

PARASITAEMIA

A quantitative measure of the percentage of erythrocytes that are parasitized.

PHARMACOKINETICS

The study of absorption, distribution, metabolism and elimination of drugs in a higher organism.

RECRUDESCENCE

The reappearance of parasites or symptoms, in the case of parasitological or clinical recrudescence, in the days following drug treatment. This is a result of incomplete clearance of the infection.

CYSTEINE PROTEASES

A class of parasite enzymes involved in crucial processes during parasite development.

PROTEIN FARNESYL TRANSFERASES

These mediate attachment of the prenyl groups farnesyl and geranylgeranyl to specific eukaryotic cell proteins.

HAEMOZOIN

An ordered crystalline assembly of β-haematin moieties produced following haemoglobin digestion in the parasite's food vacuole.

FOOD VACUOLE

An acidic organelle of erythrocytic parasites in which haemoglobin degradation takes place.

ORTHOLOGUE

A gene (or protein) with similar function to a gene (or protein) in a related species.

HAEMATOCRIT

The proportion of the volume of a sample of blood that is represented by red blood cells.

IC50

The drug concentration that produces a 50% inhibition of P. falciparum growth in vitro. This is frequently determined by calculating the concentration that produces a 50% reduction in uptake of 3H-hypoxanthine.

GIEMSA

A nucleic acid stain used to visually distinguish Plasmodium parasites from the surrounding cells.

SYNCHRONIZED CULTURES

Cultures of parasites at the same or similar stage of intracellular development.

INOCULUM

A substance or organism that is introduced into surroundings suited to cell growth. In this case this refers to introduction of a defined number of parasitized erythrocytes into in vitro culture or a susceptible rodent.

ISOBOLOGRAM

A graphical representation of growth inhibition data for two compounds, plotted as fractional IC50 values on an X–Y axis, permitting determination of whether the two compounds are synergistic, additive or antagonistic.

ANTAGONISM

An interaction between agents in which one partially or completely inhibits the effect of the other.

SCHIZOGONY

The intracellular process whereby multinucleated Plasmodium parasites differentiate to form multiple infectious forms (merozoites), which then egress from the infected cell in order to invade uninfected erythrocytes.

ED50

The drug concentration that produces a 50% reduction in parasitaemia in vivo, typically in a rodent malaria model.

BIOAVAILABILITY

The degree to which a drug is available to the body. This is influenced by how much the substance is absorbed and circulated.

SEQUESTRATION

The ability of P. falciparum to sequester in capillary beds as a result of binding of the parasitized erythrocyte to endothelial cell surface receptors. This binding is mediated by parasite-encoded variant antigens presented at the erythrocyte surface.

LEAD OPTIMIZATION

The process of chemically optimizing a compound to improve antimicrobial activity and pharmacological properties.

LEAD IDENTIFICATION

The process of identifying an acceptable lead compound with potent in vitro and in vivo activity.

PHARMACODYNAMICS

The study of the mechanisms of actions of a drug, and the relationship between how much drug is in the body and its effects.

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Fidock, D., Rosenthal, P., Croft, S. et al. Antimalarial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov 3, 509–520 (2004). https://doi.org/10.1038/nrd1416

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