Borrelidin, a potent antimalarial: stage-specific inhibition profile of synchronized cultures of Plasmodium falciparum

Ishiyama, Aki; Iwatsuki, Masato; Namatame, Miyuki; Nishihara‐Tsukashima, Aki; Sunazuka, Toshiaki; Takahashi, Yōko; Ōmura, Satoshi; Otoguro, Kazuhiko

doi:10.1038/ja.2011.6

Cited by 42 publications

(41 citation statements)

References 24 publications

(27 reference statements)

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“…Among these, we found that borrelidin exhibits excellent antimalarial activity, as previously reported (20)(21)(22). Borrelidin is a noncompetitive inhibitor of both bacterial and eukaryotic threonyl-tRNA synthetases (ThrRS) (23) and exhibits antiangiogenic (24)(25)(26), antimalarial (21,22), and antimicrobial (27) properties. The antimalarial activity of borrelidin is thought to arise from inhibition of ThrRS, which in Plasmodium, is present as a single enzyme dually targeted to cytosol and apicoplast (28).…”

Section: Significancesupporting

confidence: 78%

“…The most potent antimalarial activity was shown by borrelidin, a potent macrolide known to inhibit mammalian, bacterial, and protozoan threonyl-tRNA synthetases (ThrRS) (21,22,27,30,40). With an IC 50 of 0.97 nM, borrelidin is a more potent antimalarial compound than artemether, artesunate, or chloroquine (21,22). Its activity is thought to arise from inhibition of ThrRS (41).…”

Section: Resultsmentioning

confidence: 99%

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Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo.aminoacyl-tRNA synthetase | malaria | drug design | borrelidin | plasmodium

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Section: Significancesupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Pharmacological studies have revealed that borrelidin exhibits anti-malarial, anti-angiogenesis and antifungal activities, [33][34][35] and borrelidin is also known as a strong inhibitor of threonyl-tRNA synthetase. 36,37) Although a variety of biological activity has been reported, there are no reports related to anti-obesity effect of borrelidin.…”

Section: Resultsmentioning

confidence: 99%

Borrelidin Isolated from <i>Streptomyces</i> sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells <i>via</i> Several Factors Including GATA-Binding Protein 3

Matsuo

Kondo

Kawasaki

et al. 2015

Biological & Pharmaceutical Bulletin

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“…The drug exhibits a classic delayed-death effect typical of apicoplast-specific action. This is in contrast to the Thr-RS inhibitor borrelidin, which kills parasites rapidly and whose target Thr-RS has now been demonstrated to be dually targeted to the cytoplasm and apicoplast of P. falciparum (Ishiyama et al 2011;Jackson et al 2011). EF-Tu is an important drug target as Hoepfner et al (2012) many antibiotics interact directly with the factor.…”

Section: Translation Components As Targets For Drug Intervention Agaimentioning

confidence: 98%

Translation in Mitochondria and Apicoplasts of Apicomplexan Parasites

Gupta

Haider

Vaishya

et al. 2013

Translation in Mitochondria and Other Organelles

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Protozoan parasites of the phylum apicomplexa are the causal organisms for several important infectious diseases. They contain three cellular compartments -the cytoplasm, mitochondrion, and the relic plastid called the apicoplast, where active translation takes place. Early investigations of the components and activities of the translation machinery in parasite organelles have provided evidence for intriguing variations from other systems. Understanding these mechanisms also offers novel possibilities for drug intervention. In this article, we discuss the translation machinery in the apicoplast and mitochondrion of the apicomplexan cell, with emphasis on current knowledge from Plasmodium and Toxoplasma.

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Borrelidin, a potent antimalarial: stage-specific inhibition profile of synchronized cultures of Plasmodium falciparum

Cited by 42 publications

References 24 publications

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Borrelidin Isolated from <i>Streptomyces</i> sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells <i>via</i> Several Factors Including GATA-Binding Protein 3

Translation in Mitochondria and Apicoplasts of Apicomplexan Parasites

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