Re-Envisioning Anti-Apicomplexan Parasite Drug Discovery Approaches.

Gabriel W Rangel,Manuel Llinás

doi:10.3389/fcimb.2021.691121

Gabriel W Rangel, Manuel Llinás

Open Access

https://doi.org/10.3389/fcimb.2021.691121

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Abstract

Parasites of the phylum Apicomplexa impact humans in nearly all parts of the world, causing diseases including to toxoplasmosis, cryptosporidiosis, babesiosis, and malaria. Apicomplexan parasites have complex life cycles comprised of one or more stages characterized by rapid replication and biomass amplification, which enables accelerated evolutionary adaptation to environmental changes, including to drug pressure. The emergence of drug resistant pathogens is a major looming and/or active threat for current frontline chemotherapies, especially for widely used antimalarial drugs. In fact, resistant parasites have been reported against all modern antimalarial drugs within 15 years of clinical introduction, including the current frontline artemisinin-based combination therapies. Chemotherapeutics are a major tool in the public health arsenal for combatting the onset and spread of apicomplexan diseases. All currently approved antimalarial drugs have been discovered either through chemical modification of natural products or through large-scale screening of chemical libraries for parasite death phenotypes, and so far, none have been developed through a gene-to-drug pipeline. However, the limited duration of efficacy of these drugs in the field underscores the need for new and innovative approaches to discover drugs that can counter rapid resistance evolution. This review details both historical and current antimalarial drug discovery approaches. We also highlight new strategies that may be employed to discover resistance-resistant drug targets and chemotherapies in order to circumvent the rapid evolution of resistance in apicomplexan parasites.

Highlights

Apicomplexan parasites are prevalent all over the world and represent a major burden to global health, causing widespread diseases including cryptosporidiosis, one of the most common causes of diarrheal disease (Khalil et al, 2018), toxoplasmosis, infecting up to 30% of the global population (Montoya and Liesenfeld, 2004), and malaria, causing over 220 million clinical cases and approximately 400,000 deaths in 2019 (World Health Organization, 2019)
While many of the points made are applicable to other apicomplexan parasites, the remainder of this review will focus on antimalarial drug discovery and will offer new approaches that may be adopted to identify putative resistance-resistant antimalarial drug targets
Due to the similar activity of proguanil and 2:4-diaminopyrimidines in this new assay as well as their structural similarity, it was posited that compounds in this class might be antimalarial as well, and, screening of 2:4-diaminopyrimidine derivatives against P. gallinaceum and P. berghei led to the discovery of the antifolate pyrimethamine

Summary

Introduction

Apicomplexan parasites are prevalent all over the world and represent a major burden to global health, causing widespread diseases including cryptosporidiosis, one of the most common causes of diarrheal disease (Khalil et al, 2018), toxoplasmosis, infecting up to 30% of the global population (Montoya and Liesenfeld, 2004), and malaria, causing over 220 million clinical cases and approximately 400,000 deaths in 2019 (World Health Organization, 2019). Plasmochin had severe side-effects, screening of plasmochin analogs in P. gallinaceum for less toxic compounds eventually led to the discovery of primaquine, the most widely used 8-aminoquinolone (Wiselogle, 1946).

Results

Conclusion