Antimalarial Chemotherapy in the XXIst Century

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Background

Plasmodium parasites are known as the etiological agents of malaria, transmitted by Anopheles mosquitoes, for over a century. Yet, malaria still remains as a major health concern worldwide. Use of insecticide-treated bed nets and artemisinin-based combination therapies (ACT) have been major players in decreasing the malaria burden over the past two decades. Still, emergence of parasite resistance to ACT is a serious menace to malaria containment, and drives the need to find efficient alternatives. While most available antiplasmodials target the symptomatic blood stage of infection, malaria can only be eradicated if drugs are developed that block parasite transmission, and clear liver forms, including hypnozoites. This imperative need underpinned recent changes in the target antimalarial candidates and target antimalarial product profiles. These have fueled new approaches towards antimalarial drug discovery and development, causing an impressive enrichment of the antimalarial leads’ portfolio in the XXIst century.

An optimal antimalarial should not elicit resistance and should neutralize all parasite stages inside the human host, namely (i) hepatic forms associated to the asymptomatic onset of disease, (ii) dormant liver forms (hypnozoites) responsible for relapse in certain malaria types, (iii) blood-stage forms underlying the symptomatic phase of infection, and (iv) gametocytes, responsible for host-to-vector transmission. An ideal antimalarial should additionally be produced at low cost since malaria is mainly endemic in low-to-middle income countries. Besides conventional drug discovery approaches, cost-effective ways to accelerate identification of novel antimalarial strategies have included (i) combination therapy, by joining two or more known drugs, (ii) covalent bitherapy, by conjugating different pharmacophores, (iii) repurposing of drugs with other therapeutic indications, and (v) rescuing of known antimalarial scaffolds. This delivered a significant collection of antimalarial compounds, several of which showing potential to step into clinical trials. Yet, the enthusiasm in progressing such candidates has been cooling down and, except for tafenoquine, no new molecule has been approved for clinical use against malaria since introduction of ACT in the dawn of this century. Provided the current setting, this Research Topic is intended to convey a broad picture of the current challenges and prospects in antimalarial drug discovery and development.

Malaria is one of the “Big Three” infectious diseases, along with HIV-1/AIDS and Tuberculosis, that are prioritized by the World Health Organization. While tackling the “Big Three” is an important part of the Sustainable Development Goal 3 – Good Health and Well-Being – of the United Nations Agenda for 2030, the emergence of the COVID-19 pandemic is expected to reverse decades of improvements and lead to a 100% increase in malaria deaths in Sub-Saharan Africa. This accentuates the pressing need to contain malaria. In this scenario, the Research Topic “Antimalarial Chemotherapy in the XXIst Century” is aimed at widely covering this subject, by offering a collection of opinion articles, literature reviews, and original research papers addressing the scope and limitations of current antimalarial drug discovery and development. Contributions will be welcome which highlight antimalarial approaches investigated over the past two decades, from rational drug design to drug rescuing, repurposing, new molecular targets, targeted delivery, among many others.

Keywords: Drug Design, Malaria, Plasmodium, Rescuing, Repurposing

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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