Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells

Joshua C. Johnson, Osvaldo Martinez, Anna N. Honko, Lisa E. Hensley, Gene G. Olinger, Christopher F. Basler

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Antigen presenting cells (APCs), including macrophages and dendritic cells, are early and sustained targets of Ebola virus (EBOV) infection in vivo. Because EBOV activates mitogen-activated protein kinase (MAPK) signaling upon infection of APCs, we evaluated the effect of pyridinyl imidazole inhibitors of p38 MAPK on EBOV infection of human APCs and EBOV mediated cytokine production from human DCs. The p38 MAPK inhibitors reduced viral replication in PMA-differentiated macrophage-like human THP-1 cells with an IC50 of 4.73 μM (SB202190), 8.26 μM (p38kinhIII) and 8.21 μM (SB203580) and primary human monocyte-derived dendritic cells (MDDCs) with an IC50 of 2.67 μM (SB202190). Furthermore, cytokine production from EBOV-treated MDDCs was inhibited in a dose-dependent manner. A control pyridinyl imidazole compound failed to inhibit either EBOV infection or cytokine induction. Using an established EBOV virus-like particle (VLP) entry assay, we demonstrate that inhibitor pretreatment blocked VLP entry suggesting that the inhibitors blocked infection and replication at least in part by blocking EBOV entry. Taken together, our results indicate that pyridinyl imidazole p38 MAPK inhibitors may serve as leads for the development of therapeutics to treat EBOV infection.

Original languageEnglish (US)
Pages (from-to)102-109
Number of pages8
JournalAntiviral research
Volume107
Issue number1
DOIs
StatePublished - Jul 2014
Externally publishedYes

Keywords

  • Antigen-presenting cell
  • Dendritic cell
  • Ebola virus
  • Entry
  • p38 MAPK
  • THP-1

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Fingerprint

Dive into the research topics of 'Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells'. Together they form a unique fingerprint.

Cite this