Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor.

Détails

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Etat: Serval
Version: de l'auteur
ID Serval
serval:BIB_9466129FAB72
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor.
Périodique
Proceedings of the National Academy of Sciences of the United States of America
Auteur(s)
Kuhlmann F.M., Robinson J.I., Bluemling G.R., Ronet C., Fasel N., Beverley S.M.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Statut éditorial
Publié
Date de publication
31/01/2017
Peer-reviewed
Oui
Volume
114
Numéro
5
Pages
E811-E819
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The endogenous double-stranded RNA (dsRNA) virus Leishmaniavirus (LRV1) has been implicated as a pathogenicity factor for leishmaniasis in rodent models and human disease, and associated with drug-treatment failures in Leishmania braziliensis and Leishmania guyanensis infections. Thus, methods targeting LRV1 could have therapeutic benefit. Here we screened a panel of antivirals for parasite and LRV1 inhibition, focusing on nucleoside analogs to capitalize on the highly active salvage pathways of Leishmania, which are purine auxotrophs. Applying a capsid flow cytometry assay, we identified two 2'-C-methyladenosine analogs showing selective inhibition of LRV1. Treatment resulted in loss of LRV1 with first-order kinetics, as expected for random virus segregation, and elimination within six cell doublings, consistent with a measured LRV1 copy number of about 15. Viral loss was specific to antiviral nucleoside treatment and not induced by growth inhibitors, in contrast to fungal dsRNA viruses. Comparisons of drug-treated LRV1 <sup>+</sup> and LRV1 <sup>-</sup> lines recapitulated LRV1-dependent pathology and parasite replication in mouse infections, and cytokine secretion in macrophage infections. Agents targeting Totiviridae have not been described previously, nor are there many examples of inhibitors acting against dsRNA viruses more generally. The compounds identified here provide a key proof-of-principle in support of further studies identifying efficacious antivirals for use in in vivo studies of LRV1-mediated virulence.

Mots-clé
Animals, Antiviral Agents/pharmacology, Capsid Proteins/genetics, Capsid Proteins/metabolism, Leishmania braziliensis/virology, Leishmania guyanensis/virology, Leishmaniasis/parasitology, Leishmaniavirus/drug effects, Leishmaniavirus/genetics, Leishmaniavirus/metabolism, Mice, Inbred C57BL, Nucleosides/pharmacology, Nucleotides/pharmacology, chemotherapy, endobiont virus, trypanosomatid protozoan parasite, viral segregation, virulence
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2017 14:59
Dernière modification de la notice
08/05/2019 22:13
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