Assessing the in vitro resistance development in Enterovirus 71 in the context of combination antiviral treatment
| Autor: | Kristina Lanko, Leen Delang, Chenyan Shi, Johan Neyts, Shivaprasad Patil, Carmen Mirabelli, Jelle Matthijnssens |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
education.field_of_study Protease biology Nucleoside analogue 030306 microbiology medicine.medical_treatment viruses Population Context (language use) biology.organism_classification medicine.disease_cause Virology Virus 3. Good health 03 medical and health sciences Capsid medicine Enterovirus 71 Enterovirus education 030304 developmental biology medicine.drug |
| DOI: | 10.1101/2020.02.10.935536 |
| Popis: | There are currently no antivirals available to treat infection with enterovirus A71 (EV-A71) or any other enterovirus. The extensively studied capsid binders select rapidly for drug-resistant variants. We here explore whether the combination of two direct-acting enterovirus inhibitors with a different mechanism of action may delay or prevent resistance development to the capsid binders. To that end, the in vitro dynamics of resistance development to the capsid binder pirodavir was studied either alone or in combination with (i) a viral 2C-targeting compound (SMSK_0213), (ii) a viral 3C-protease inhibitor (rupintrivir) or (iii) a viral RNA-dependent RNA polymerase (RdRp) inhibitor [7-deaza-2’C-methyladenosine (7DMA)]. We demonstrate that combining pirodavir with either rupintrivir or the nucleoside analogue 7DMA delays the development of resistance to pirodavir and that no resistance to the protease or polymerase inhibitor develops. The combination of pirodavir with the 2C inhibitor results in a double-resistant virus population. The deep sequencing analysis of resistant populations revealed that even though resistant mutations are present in less than 30% of the population, this still provides the resistant phenotype. |
| Databáze: | OpenAIRE |
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