NDLI: The Plasmodium falciparum cytoplasmic translation apparatus: a promising therapeutic target not yet exploited by clinically approved anti-malarials

Content Provider	Springer Nature : BioMed Central
Author	Sheridan, Christine Moore Garcia, Valentina E. Ahyong, Vida DeRisi, Joseph L.
Abstract	Background The continued spectre of resistance to existing anti-malarials necessitates the pursuit of novel targets and mechanisms of action for drug development. One class of promising targets consists of the 80S ribosome and its associated components comprising the parasite translational apparatus. Development of translation-targeting therapeutics requires a greater understanding of protein synthesis and its regulation in the malaria parasite. Research in this area has been limited by the lack of appropriate experimental methods, particularly a direct measure of parasite translation. Methods An in vitro method directly measuring translation in whole-cell extracts from the malaria parasite Plasmodium falciparum, the PfIVT assay, and a historically-utilized indirect measure of translation, S35-radiolabel incorporation, were compared utilizing a large panel of known translation inhibitors as well as anti-malarial drugs. Results Here, an extensive pharmacologic assessment of the PfIVT assay is presented, using a wide range of known inhibitors demonstrating its utility for studying activity of both ribosomal and non-ribosomal elements directly involved in translation. Further, the superiority of this assay over a historically utilized indirect measure of translation, S35-radiolabel incorporation, is demonstrated. Additionally, the PfIVT assay is utilized to investigate a panel of clinically approved anti-malarial drugs, many with unknown or unclear mechanisms of action, and show that none inhibit translation, reaffirming Plasmodium translation to be a viable alternative drug target. Within this set, mefloquine is unambiguously found to lack translation inhibition activity, despite having been recently mischaracterized as a ribosomal inhibitor. Conclusions This work exploits a direct and reproducible assay for measuring P. falciparum translation, demonstrating its value in the continued study of protein synthesis in malaria and its inhibition as a drug target.
Related Links	https://malariajournal.biomedcentral.com/counter/pdf/10.1186/s12936-018-2616-7.pdf
Ending Page	13
Page Count	13
Starting Page	1
File Format	HTM / HTML
ISSN	14752875
DOI	10.1186/s12936-018-2616-7
Journal	Malaria Journal
Issue Number	1
Volume Number	17
Language	English
Publisher	BioMed Central
Publisher Date	2018-12-12
Access Restriction	Open
Subject Keyword	Parasitology Tropical Medicine Infectious Diseases Entomology Microbiology Public Health 80S ribosome Translation In vitro translation assay Antimalarial drugs Mefloquine
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Parasitology
Journal Impact Factor	2.4/2023
5-Year Journal Impact Factor	2.6/2023

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The Plasmodium falciparum cytoplasmic translation apparatus: a promising therapeutic target not yet exploited by clinically approved antimalarials

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The Plasmodium falciparum cytoplasmic translation apparatus: a promising therapeutic target not yet exploited by clinically approved anti-malarials

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