Angela Oliva, Maria, Tosat-Bitrian, Carlota, Barrado-Gil, Lucia, Bonato, Francesca, Galindo, Inmaculada, Garaigorta, Urtzi, Alvarez-Bernad, Beatriz, Paris-Ogayar, Rebeca, Lucena-Agell, Daniel, Francisco Gimenez-Abian, Juan et al (show 6 more authors)
(2022)
Effect of Clinically Used Microtubule Targeting Drugs on Viral Infection and Transport Function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23 (7).
3448-.
Abstract
Microtubule targeting agents (MTAs) have been exploited mainly as anti-cancer drugs because of their impact on cellular division and angiogenesis. Additionally, microtubules (MTs) are key structures for intracellular transport, which is frequently hijacked during viral infection. We have analyzed the antiviral activity of clinically used MTAs in the infection of DNA and RNA viruses, including SARS-CoV-2, to find that MT destabilizer agents show a higher impact than stabilizers in the viral infections tested, and FDA-approved anti-helminthic benzimidazoles were among the most active compounds. In order to understand the reasons for the observed antiviral activity, we studied the impact of these compounds in motor proteins-mediated intracellular transport. To do so, we used labeled peptide tools, finding that clinically available MTAs impaired the movement linked to MT motors in living cells. However, their effect on viral infection lacked a clear correlation to their effect in motor-mediated transport, denoting the complex use of the cytoskeleton by viruses. Finally, we further delved into the molecular mechanism of action of Mebendazole by combining biochemical and structural studies to obtain crystallographic high-resolution information of the Mebendazole-tubulin complex, which provided insights into the mechanisms of differential toxicity between helminths and mammalians.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | antivirals, microtubule targeting drugs, SARS-CoV-2, mebendazole-tubulin complex crystal structure |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 18 Oct 2022 09:55 |
| Last Modified: | 18 Jan 2023 20:36 |
| DOI: | 10.3390/ijms23073448 |
| Open Access URL: | https://doi.org/10.3390/ijms23073448 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165583 |
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