LATE-BREAKING ABSTRACT: Effects of a single treatment with PC786, a novel inhibitor of respiratory syncytial virus replication, on viral load and biomarkers in fully differentiated human bronchial epithelial cells

Abstract

Addition of RSV A2 to fully-differentiated air-liquid interface cultured human bronchial epithelial cells resulted in a robust infection which generated amplified viral titres and measurable pro-inflammatory biomarkers. The novel first-in-class anti-RSV agent, PC786, showed a concentration dependent inhibition of RSV replication determined by plaque assay following a single apical treatment on Day 1 post-infection, reducing viral titres to below detectable limits the following day. Viral titres remained undetectable for 2 or 5 days when treated with either 0.1 or 0.5µg/ml of PC786, respectively. PCR products showed similar kinetics to the RSV virus titre determined by plaque assay. RSV A2 infection also induced several pro-inflammatory cytokines (RANTES, IL-6, IL-8, IP-10), mucin and double stranded DNA, a marker of epithelial cell injury. A single treatment of PC786 on Day 1 post infection delayed the expression of each of these biomarkers. In addition, a good correlation was found between PC786 content within cells and anti-viral activity determined by PCR in apical wash. Thus, PC786 showed rapid onset of action and produced sustained inhibition of RSV replication and associated biomarker expression following only a single treatment post infection, and the anti-viral activity was correlated well with PC786 content within cells. Therefore PC786 has the potential to be an effective treatment for RSV infection in humans, and the clear PK-PD relationship observed in this study has the potential to help to predict efficacy of PC786 by measuring local epithelial concentrations of the drug in vivo.