A new microtubule-stabilizing agent shows potent antiviral effects against African swine fever virus with no cytotoxicity
| Autor: | João Sette Whitaker Ferreira, Tamara Hakobyan, Fernando Ferreira, Hovakim Zakaryan, Harutyun Sahakyan, Elmira K. Hakobyan, Arsen Sargsyan, Zaven A. Karalyan, Anush A. Hovakimyan, Astghik Hakobyan, Grigor Arakelov, Roza Izmailyan, Marco Neves, L.O. Abroyan, Garri Chilingaryan, Erik Arabyan, Andre Serobian, Elina Arakelova, Karen Nazaryan, Samvel N. Sirakanyan |
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| Přispěvatelé: | Repositório da Universidade de Lisboa |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Swine Epidemiology animal diseases 030106 microbiology Immunology Microtubule Virus Replication Antiviral Agents Microtubules Microbiology African swine fever virus 03 medical and health sciences antivirals Tubulin Virology Chlorocebus aethiops Drug Discovery Animals African Swine Fever Cytotoxicity Vero Cells biology Protein Stability screening General Medicine Antivirals biology.organism_classification African Swine Fever Virus 030104 developmental biology Infectious Diseases tubulin Screening biology.protein Fatal disease Original Article Parasitology Research Article microtubule |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP Emerging Microbes & Infections article-version (VoR) Version of Record |
| ISSN: | 2222-1751 |
| DOI: | 10.1080/22221751.2021.1902751 |
| Popis: | © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. African swine fever virus (ASFV) is the causal agent of a fatal disease of domestic swine for which no effective antiviral drugs are available. Recently, it has been shown that microtubule-targeting agents hamper the infection cycle of different viruses. In this study, we conducted in silico screening against the colchicine binding site (CBS) of tubulin and found three new compounds with anti-ASFV activity. The most promising antiviral compound (6b) reduced ASFV replication in a dose-dependent manner (IC50 = 19.5 μM) with no cellular (CC50 > 500 μM) and animal toxicity (up to 100 mg/kg). Results also revealed that compound 6b interfered with ASFV attachment, internalization and egress, with time-of-addition assays, showing that compound 6b has higher antiviral effects when added within 2-8 h post-infection. This compound significantly inhibited viral DNA replication and disrupted viral protein synthesis. Experiments with ASFV-infected porcine macrophages disclosed that antiviral effects of the compound 6b were similar to its effects in Vero cells. Tubulin polymerization assay and confocal microscopy demonstrated that compound 6b promoted tubulin polymerization, acting as a microtubule-stabilizing, rather than a destabilizing agent in cells. In conclusion, this work emphasizes the idea that microtubules can be targets for drug development against ASFV. This work of E. A., A. H., and H. Z. was supported by the RA MESCS Science Committee, Armenia [grant number 19YR-1F039]; the work of F. F. was supported by the FCT – Fundação para a Ciência e a Tecnologia, Portugal [grant number UIDB/00276/2020]. |
| Databáze: | OpenAIRE |
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