Avermectins Inhibit Replication of Parvovirus B19 by Disrupting the Interaction Between Importin α and Non-Structural Protein 1

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Abstract
Human parvovirus B19 (B19V) is a major human pathogen in which the ssDNA genome is replicated within the nucleus of infected human erythroid progenitor cells (EPCs) through a process involving both cellular and viral proteins, including the non-structural protein (NS)1. We previously characterized the interaction between NS1 classical nuclear localization signal (cNLS: GACHAKKPRIT-182) and host cell importin (IMP)α and proposed it as a potential target for antiviral drug development. Here, we further extend on such findings. First, we demonstrate that NS1 nuclear localization is required for viral production since introducing the K177T substitution in a cloned, infectious viral genome resulted in a non-viable virus. Secondly, we demonstrate that the antiparasitic drug ivermectin (IVM), known to inhibit the IMPα/β dependent nuclear import pathway, could impair the NS1-NLS:IMPα interaction and suppress viral replication in UT7/EpoS1 cells in a dose-dependent manner. We also show that a panel of structurally related avermectins (AVMs) can dissociate the NS1-NLS:IMPα complex with half-maximal inhibitory concentrations in the nanomolar range. Among them, Eprinomectin emerged as the most selective inhibitor of B19V replication, with a selectivity index of c. 5.0. However, when tested in EPCs generated from peripheral blood mononuclear cells, which constitute a cellular population close to the natural target cells in bone marrow, the inhibitory effect of IVM and Eprinomectin was demonstrated to a lesser extent, and both compounds exhibited high toxicity, thus highlighting the need for more specific inhibitors of the NS1-NLS:IMPα interaction.
Funding Information
  • Italian Ministry for Universities and Research (MUR) Progetto PRIN (2022 cod. 2022F2YJNK—Acr. INTERROGA, CUP: C53D23003110006, PNRR PE13—INF-ACT One Health. PE00000007, CUP J33C22002870005)
  • Monash University (2022 cod. 2022F2YJNK—Acr. INTERROGA, CUP: C53D23003110006, PNRR PE13—INF-ACT One Health. PE00000007, CUP J33C22002870005)
  • University of Padua (2022 cod. 2022F2YJNK—Acr. INTERROGA, CUP: C53D23003110006, PNRR PE13—INF-ACT One Health. PE00000007, CUP J33C22002870005)

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