Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor

Abstract

Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC50], <0.09 to 0.71 nM) and RSV-B (IC50, 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro. In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC50, 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections.

Late therapeutic intervention with a respiratory syncytial virus L‐protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium

“…We have previously published a ‘basic’ or ‘standard’ biological data set outlining the profile of PC786, using cancerous or immortalised cell lines in vitro and mouse or cotton rat in vivo , which are semi‐permissive to human RSV infection (Coates et al, ). However, the viral replication period is too short in all of these systems to evaluate a therapeutic treatment regimen, as opposed to prophylaxis.…”

“…PC786 ( N ‐(2‐fluoro‐6‐methylphenyl)‐6‐(4‐(5‐methyl‐2‐(7‐oxa‐2‐azaspiro[3.5]nonan‐2‐yl)nicotinamido)benzoyl)‐5,6‐dihydro‐4 H ‐benzo[b]thieno[2,3‐d]azepine‐2‐carboxamide) is a novel non‐nucleoside low MW RSV polymerase inhibitor, which demonstrated profound inhibition of both RSV A and B strain replication coupled with a long duration of action, which has been optimized for topical inhalation treatment (Coates et al, ). It is currently in early clinical development (http://clinicaltrials.gov identifier: NCT03236233, NCT03382431) (ClinicalTrial.gov, ; ClinicalTrial.gov, ).…”

Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference

“…ALS-008176 (lumicitabine) is an oral nucleoside analog that demonstrated proof of concept in a human RSV challenge model (DeVincenzo et al, 2015). Finally, PC786 is a nonnucleoside L protein polymerase inhibitor that has undergone preclinical characterization (Coates et al, 2017). Other antivirals are also in clinical development including those representing the fusion inhibitor class and replication inhibitor class.…”

Innovation and trends in the development and approval of antiviral medicines: 1987–2017 and beyond

“…Replication inhibitors represent the third class of RSV drug candidates. Lumicitabine and PC-786 bind to the polymerase L subunit (Deval et al, 2015;Coates et al, 2017), whereas EDP-938 interferes with the nucleoprotein N. Lumicitabine is currently the only RSV replication inhibitor with demonstrated clinical proof-of-concept efficacy (DeVincenzo et al, 2015).…”