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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.Malaria case numbers are rising globally and there is a vital need for new medicines that overcome the emergence of drug resistance. This Review describes the current landscape of small-molecule antimalarial therapies and the methods used to discover them as well as perspectives on approaches to find new targets and treatments.

Climate change is already affecting vector-borne disease transmission and spread, and its impacts are likely to worsen. In the face of ongoing climate change, we must intensify efforts to prevent and control vector-borne diseases.

Leishmaniasis (visceral and cutaneous), Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries. Although the situation has improved for human African trypanosomiasis, there remains an urgent need for new medicines to treat leishmaniasis and Chagas disease; the clinical development pipeline is particularly sparse for Chagas disease. In this Review, we describe recent advances in our understanding of the biology of the causative pathogens, particularly from the drug discovery perspective, and we explore the progress that has been made in the development of new drug candidates and the identification of promising molecular targets. We also explore the challenges in developing new clinical candidates and discuss potential solutions to overcome such hurdles.In this Review, Gilbert and colleagues discuss recent progress in drug discovery for kinetoplastid diseases and how an improved understanding of parasite biology affects the drug discovery process

Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa 1 – 4 . Here we genotyped the P. falciparum K13 ( Pfkelch13 ) propeller domain, mutations in which can mediate artemisinin resistance 5 , 6 , in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda 7 . While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13 -mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa. Identification in Rwanda of mutations in Plasmodium falciparum capable of conferring in vitro resistance to artemisinin, an essential medicine for the treatment of malaria, underscore the crucial need for surveillance in Africa to safeguard efficacy of life-saving therapies.

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms. Comparative study of 81 genomes of parasitic and non-parasitic worms identifies gene family births and expanded gene families at key nodes in the phylogeny that are relevant to parasitism and proteins historically targeted for drug development.

Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, and antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity to ARTs is emerging, making it critically important to understand the mechanism of action of ARTs. Here we demonstrate that dihydroartemisinin (DHA), the clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, and compromising parasite proteasome function. The consequent accumulation of proteasome substrates, i.e., unfolded/damaged and polyubiquitinated proteins, activates the ER stress response and underpins DHA-mediated killing. Specific inhibitors of the proteasome cause a similar build-up of polyubiquitinated proteins, leading to parasite killing. Blocking protein synthesis with a translation inhibitor or inhibiting the ubiquitin-activating enzyme, E1, reduces the level of damaged, polyubiquitinated proteins, alleviates the stress response, and dramatically antagonizes DHA activity. Artemisinin (ART) is a widely used antimalarial drug, but its mechanism of action is poorly understood. Here, Bridgford et al. show that ART kills parasites by a two-pronged mechanism, causing protein damage and compromising proteasome function, and that accumulation of proteasome substrates activates the ER stress response.

Key Points Trypanosomatid parasites cause several neglected diseases in humans and animals that range in severity from comparatively mild to nearly invariably fatal. The organisms that are responsible for human diseases include Trypanosoma brucei , which causes human African trypanosomiasis (HAT), Trypanosoma cruzi , which causes Chagas disease, and Leishmania spp., which cause leishmaniasis. The current drugs for the treatment of trypanosomatid diseases are unsatisfactory owing to several reasons: poor efficacy, drug resistance, toxic side effects and parenteral administration. Hence, new drugs are urgently required. The drug discovery process typically takes 10–15 years. This process should be guided by target product profiles (TPPs) that define the key features and requirements for a new drug, such as route of administration, length of treatment, cost and safety margins. The drug discovery process starts with target-based or phenotypic (whole-cell) approaches. In the former, compounds are screened against a molecular target (usually an enzyme); in the latter, compounds are screened directly against the intact parasite growing in culture. In general, there has been a very poor success rate in target-based approaches against trypanosomatids, despite some unique biochemical and metabolic features in trypanosomatid parasites. There are very few robustly validated drug targets. Phenotypic approaches have led to some promising compounds, following the optimization of the initial hits. Some of these are now in clinical development for the treatment of HAT. Another approach for drug discovery is to reposition drugs from other disease areas. In some cases this has been successful. There is still a need to refine the drug discovery pathway for Chagas disease, in cellular and animal models in particular, to improve the identification of compounds that can cure patients. There is still a long way to go, but good progress is being made in drug discovery to find potential new drugs to treat trypanosomatid diseases. Trypanosomatid parasites can cause life-threatening diseases, such as human African trypanosomiasis, leishmaniasis and Chagas disease. In this Review, Gilbert and colleagues discuss the drug discovery landscape and describe some of the challenges that are involved in the development of new drugs to treat these diseases. The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addition, we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.

Key Points Apicomplexa are unicellular eukaryotic parasites that exhibit two types of secretory organelle at their apical pole and a membranous system that underlies their plasma membrane. Apicomplexa are obligate intracellular parasites that use a substrate-dependent gliding motility to move and to actively enter host cells, and to egress from the infected cells. Motility by Apicomplexa relies on the translocation of parasite surface adhesins from the apical pole, from where they are secreted to the posterior pole in a process powered by a machinery termed the glideosome. The rearward translocation of the adhesins bound to host cell receptors involves the actomyosin system, which propels the parasite forward. The invasion of host cells involves the formation of a moving junction at the point of apposition between the plasma membrane of the parasite and the host cell. Both ligands and receptors are secreted by the parasite, and they form a solid platform to support the force applied by the parasite during penetration. A tightly regulated signalling cascade coordinates the apical secretion of microneme proteins and the activation of the glideosome, which leads to gliding motility. Apicomplexa include important human pathogens and possess a unique cellular machinery that promotes gliding motility and is called the glideosome. In this Review, Soldati-Favre and colleagues discuss the principles that govern gliding motility, the characterization of the molecular machinery that comprises the glideosome, and its impact on parasite invasion and egress from infected cells. Protozoan parasites have developed elaborate motility systems that facilitate infection and dissemination. For example, amoebae use actin-rich membrane extensions called pseudopodia, whereas Kinetoplastida are propelled by microtubule-containing flagella. By contrast, the motile and invasive stages of the Apicomplexa — a phylum that contains the important human pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis) — have a unique machinery called the glideosome, which is composed of an actomyosin system that underlies the plasma membrane. The glideosome promotes substrate-dependent gliding motility, which powers migration across biological barriers, as well as active host cell entry and egress from infected cells. In this Review, we discuss the discovery of the principles that govern gliding motility, the characterization of the molecular machinery involved, and its impact on parasite invasion and egress from infected cells.

Almost any warm-blooded creature can be an intermediate host for Toxoplasma gondii . However, sexual reproduction of T . gondii occurs only in felids, wherein fertilisation of haploid macrogametes by haploid microgametes, results in diploid zygotes, around which a protective wall develops, forming unsporulated oocysts. Unsporulated oocysts are shed in the faeces of cats and meiosis gives rise to haploid sporozoites within the oocysts. These, now infectious, sporulated oocysts contaminate the environment as a source of infection for people and their livestock. RNA-Seq analysis of cat enteric stages of T . gondii uncovered genes expressed uniquely in microgametes and macrogametes. A CRISPR/Cas9 strategy was used to create a T . gondii strain that exhibits defective fertilisation, decreased fecundity and generates oocysts that fail to produce sporozoites. Inoculation of cats with this engineered parasite strain totally prevented oocyst excretion following infection with wild-type T . gondii , demonstrating that this mutant is an attenuated, live, transmission-blocking vaccine.

Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world’s poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.