Antimalarial drug discovery: progress and approaches

Abstract

Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing convenience. Discovery efforts have yielded a variety of new molecules, many with novel modes of action, and the most advanced are in late-stage clinical development. These discoveries have led to a deeper understanding of how antimalarial drugs act, the identification of a new generation of drug targets, and multiple structure-based chemistry initiatives. The limited pool of funding means it is vital to prioritize new drug candidates. They should exhibit high potency, a low propensity for resistance, a pharmacokinetic profile that favours infrequent dosing, low cost, preclinical results that demonstrate safety and tolerability in women and infants, and preferably the ability to block Plasmodium transmission to Anopheles mosquito vectors. In this Review, we describe the approaches that have been successful, progress in preclinical and clinical development, and existing challenges. We illustrate how antimalarial drug discovery can serve as a model for drug discovery in diseases of poverty.

Fig. 1 |. Malaria therapies in the context of the Plasmodium parasite lifecycle.

During its blood meal on a human host, the female Anopheles species mosquito delivers sporozoites that enter the skin and subsequently target liver cells (hepatocytes). Within the liver, the parasite matures into schizonts (or dormant hypnozoites for Plasmodium vivax and Plasmodium ovale), followed by bursting merozoites that invade erythrocytes (the asexual blood stage). The parasite forms a ring in each erythrocyte that grows into a trophozoite with an acidic digestive vacuole that digests haemoglobin to liberate peptides and amino acids required for protein synthesis. These parasites mature into multinucleated schizonts, from which thousands of merozoites rupture, allowing for rapid replication as they reinvade new red blood cells. Small percentages of merozoites differentiate into male and female gametocytes to initiate the sexual transmission stage, where parasites are ingested by a female mosquito during its blood meal to continue the cycle. Antimalarial drugs that act on the asexual blood stage are categorized as target candidate profile 1 (TCP-1), whereas molecules active against liver-stage hypnozoites (P. vivax) or hepatic schizonts are in categories TCP-3 and TCP-4, respectively. Drugs that block transmission to the mosquito by inhibiting gametocytes are TCP-5 compounds, and those that block transmission by targeting the insect vector are TCP-6 (endectocides). Two or more compounds are combined into clinical therapies with target product profile 1 (TPP-1) and TPP-2 (ref. 240). TPP-1 focuses on drugs for chemotherapeutic treatment of acute uncomplicated malaria in children or adults, using compounds with TCP-1; if possible, TCP-3, TCP-4 and TCP-5 compounds are added to reduce relapse, provide post-treatment prophylaxis and block transmission. TPP-2 focuses on prevention, in high-transmission areas or during epidemics, and gives protection via TCP-1 and, ideally, TCP-4 for prophylaxis and TCP-5 to clear gametocytaemia in asymptomatic individuals. Antimalarials approved for clinical use are listed for each TCP category.

Fig. 2 |. Antimalarial drug discovery and development pipeline.

Drug candidates in preclinical exploratory phase, human volunteer phase and patient exploratory phase as well as approved drugs are listed. They are grouped in rows according to their target candidate profile (TCP), which represents the stage of disease being targeted. Monoclonal antibodies MAM01 (ATRC-501), L9LS and CIS43LS block hepatocyte infection from sporozoites. Ruxolitinib is an immunomodulator and is being tested in combination with antimalarial therapy to modulate the long-term host immune response.