Anti-viral drug design: an integrative approach to targeting the M2-1 protein of human respiratory syncytial virus (hRSV)
Year: 2016
Type: other
Abstract: Human respiratory syncytial virus (HRSV) is the leading cause of lower respiratory tract illness in young children and the immunocompromised, with over 250,000 annual fatalities worldwide. HRSV-mediated diseases are especially prevalent in developing countries, where no financially viable treatment exists. The M2-1 protein of HRSV represents a potential anti-viral target for the treatment of HRSV-mediated diseases. M2-1 is a transcription anti-terminator with a critical role in viral gene expression. M2-1 binds both viral RNA and the polymerase co-factor phosphoprotein, and these interactions are essential for its anti-termination activity. Using computational, structural and functional methods we identified potential anti-viral compounds for the M2-1 protein of HRSV. We solved the crystal structure of M2-1 in complex with a phosphoprotein peptide and used structure based drug design (SBDD) of the interaction interface to identify potential hit compounds. Computationally derived hit compounds were further assessed through biophysical, structural and in cellulo methods. SBDD identified hit compounds that significantly inhibited HRSV infectivity. Subsequent synthetic chemistry was used to generate libraries of molecules to establish structure-activity relationships as well as assess their pharmacokinetic properties. In addition, resistance studies using live HRSV were performed to characterize the mode of compound action, as well as to better understand the viral response to the selected inhibitors. Structural modelling of the bovine RSV M2-1, a huge economic burden for the cattle industry, showed structural similarities with HRSV M2-1. The work presented here represents an effective strategy to rationally design anti-viral compounds for the M2-1 protein of HRSV with potential applications for other related viruses.
Authors: Rachel Dods, Kavestri Yegambaram, Andrew Buckley, Roger Taylor, Rachel Trowbridge, Jean-Francois Eleouet, Richard Foster, John Barr
Institution: University of Leeds
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W2953589245