Discovery of Ziresovir as a Potent, Selective, and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor

  • J Med Chem. 2019 Jul 11;62(13):6003-6014. doi: 10.1021/acs.jmedchem.9b00654.
Xiufang Zheng  1 ,  Lu Gao  1 ,  Lisha Wang  1 ,  Chungen Liang  1 ,  Baoxia Wang  1 ,  Yongfu Liu  1 ,  Song Feng  1 ,  Bo Zhang  1 ,  Mingwei Zhou  1 ,  Xin Yu  1 ,  Kunlun Xiang  1 ,  Li Chen  1 ,  Tao Guo  2 ,  Hong C Shen  1 ,  Gang Zou  3 ,  Jim Zhen Wu  3 ,  Hongying Yun  1
Affiliations
  • 1. Roche Pharma Research and Early Development , Roche Innovation Center Shanghai , Building 5, 720 Cailun Road , Shanghai 201203 , China.
  • 2. International Discovery Service Unit, Research Service Division , WuXi AppTec (Shanghai) Co., Ltd. , Lane 31, Yiwei Road, Waigaoqiao , Shanghai , 200131 , China.
  • 3. Ark Biosciences Inc. , 780 Cailun Road, Suite 701, ZhangJiang Hitech Park, Pudong , Shanghai 201203 , China.
PMID: 31194544 DOI: 10.1021/acs.jmedchem.9b00654
Abstract

Ziresovir (RO-0529, AK0529) is reported here for the first time as a promising respiratory syncytial virus (RSV) fusion (F) protein inhibitor that currently is in phase 2 clinical trials. This article describes the process of RO-0529 as a potent, selective, and orally bioavailable RSV F protein inhibitor and highlights the in vitro and in vivo anti-RSV activities and pharmacokinetics in animal species. RO-0529 demonstrates single-digit nM EC50 potency against laboratory strains, as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral Infection. RO-0529 was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell-cell fusion in cellular assays.

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