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Analysis of institutional authors

González Azcárate, IsabelAuthorMarin-Garcia, PAuthor

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September 27, 2022
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Article

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

Publicated to: Proceedings Of The National Academy Of Sciences Of The United States Of America. 111 (51): E5508-E5517 - 2014-12-23 111(51), DOI: 10.1073/pnas.1405994111

Authors:

Novoa, EM; Camacho, N; Tor, A; Wilkinson, B; Moss, S; Marín-García, P; Azcárate, IG; Bautista, JM; Mirando, AC; Francklyn, CS; Varon, S; Royo, M; Cortés, A; de Pouplana, LR
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Affiliations

Bioengn Biomat & Nanomed Network Ctr, Barcelona 08028, Catalonia, Spain - Author
Biot Technol Ltd, Cambridge CB21 6AD, England - Author
Catalan Inst Res & Adv Studies, Barcelona 08010, Catalonia, Spain - Author
Inst Res Biomed, Barcelona 08028, Catalonia, Spain - Author
Isomerase Therapeut Ltd, Cambridge CB10 1XL, England - Author
Rey Juan Carlos Univ, Hlth Sci Sch, Med Immunol Unit, Alcorcon 28922, Madrid, Spain - Author
Univ Barcelona, Combinatorial Chem Unit, E-08028 Barcelona, Catalonia, Spain - Author
Univ Complutense Madrid, Dept Biochem & Mol Biol 4, E-28040 Madrid, Spain - Author
Univ Complutense Madrid, Res Inst Hosp Octubre 12, E-28040 Madrid, Spain - Author
Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA - Author
Univ Vermont, Coll Med, Dept Microbiol & Mol Genet, Burlington, VT 05405 USA - Author
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Abstract

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.
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Keywords

2 aminocyclopentanecarboxylic acidAmino acid transfer rna ligaseAmino acid transfer rna ligase inhibitorAmino acyl-trna synthetasesAminoacyl-trna synthetaseAminoacylationAnimalAnimal experimentAnimal modelAnimalsAntagonists and inhibitorsAntifungalAntimalarial activityAntimalarial agentAntimalarial-drug discoveryAntimalarialsApicoplastArticleBc 194Bc 195Bc 196Bc 220Bc 240BiosynthesisBorrelidinCispentacinContributesControlled studyDrug designDrug effectsEnzyme inhibitorEnzyme inhibitorsGlutamate transfer rna ligaseGlutamine transfer rna ligaseHek293 cell lineHigh performance liquid chromatographyHumanHuman cellHumansIc50In vitro studyIn vivo studyIsoleucine transfer rna ligaseLeucine transfer rna ligaseLigase inhibitorLimit of detectionLysine transfer rna ligaseMalariaMalaria, falciparumMechanismMiceMouseMupirocinMusNonhumanPlasmodiumPlasmodium falciparumPlasmodium yoeliiPolyacrylamide gel electrophoresisProline transfer rnaPseudomonic acidResistantRna translationSerine transfer rna ligaseStructure activity relationThreonine transfer rnaTyrosine transfer rna ligaseUnclassified drug

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Proceedings Of The National Academy Of Sciences Of The United States Of America due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2014, it was in position 4/57, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.69. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.39 (source consulted: FECYT Mar 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-12-25, the following number of citations:

  • WoS: 63
  • Scopus: 72
  • Europe PMC: 44
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-12-25:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 100.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 100 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 59.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).
  • The number of mentions in news outlets: 7 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United Kingdom; United States of America.

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Awards linked to the item

We thank the Peptide Synthesis Unit of the Bioengineering Biomaterial and Nanomedicine Networking Center at Barcelona Science Park. This work was supported by Spanish Ministry of Education and Science Grants BIO2009-09776 and Proyectos Internacionales Proyectos Bilaterales Primer Plazo (PRI-PIBIN)-2011-1279 (to L.R.d.P.) and BIO2010-17039 (to J.M.B.); European Union Grant MEPHITIS-223024 (to L.R.d.P.); and National Institute of General Medical Sciences Grant 2RO1 GM54899 (to C.S.F.). E.M.N. was supported by a La Caixa/IRB International PhD Programme fellowship and is currently supported by Human Frontier Science Program Postdoctoral Fellowship LT000307/2013. A.C. M. is supported by National Institute of Environmental Health Sciences Training Grant T32 ES007122-23.
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