Comparative study of a 3CL pro inhibitor and remdesivir against both major SARS-CoV-2 clades in human airway models.

作者: Maren de Vries , Adil S Mohamed , Rachel A Prescott , Ana M Valero-Jimenez , Ludovic Desvignes

DOI: 10.1101/2020.08.28.272880

关键词:

摘要: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19), a pandemic that has claimed over 700,000 human lives. The only SARS-CoV-2 antiviral, for emergency use, remdesivir, targeting viral polymerase complex. PF-00835231 pre-clinical lead compound with an alternate target, main protease 3CL pro (M ). Here, we perform comparative analysis and remdesivir in A549 +ACE2 cells, using isolates two major clades. antiviral both clades, and, this assay, statistically more potent than remdesivir. A time-of-drug-addition approach delineates timing early life cycle steps validates PF-00835231's time action. Both potently inhibit polarized airway epithelial cultures. Thus, our study provides vitro evidence potential as effective SARS-CoV-2, addresses concerns from non-human models, supports further studies compound.

参考文章(65)
Mark J. Gadlage, Mark R. Denison, Exchange of the Coronavirus Replicase Polyprotein Cleavage Sites Alters Protease Specificity and Processing Journal of Virology. ,vol. 84, pp. 6894- 6898 ,(2010) , 10.1128/JVI.00752-10
EHUD LAVI, QIAN WANG, SUSAN R. WEISS, NICHOLAS K. GONATAS, Syncytia Formation Induced by Coronavirus Infection Is Associated with Fragmentation and Rearrangement of the Golgi Apparatus Virology. ,vol. 221, pp. 325- 334 ,(1996) , 10.1006/VIRO.1996.0382
Naoto Suzuyama, Miki Katoh, Toshiyuki Takeuchi, Sumie Yoshitomi, Tomoaki Higuchi, Satoru Asashi, Tsuyoshi Yokoi, Species Differences of Inhibitory Effects on P‐glycoprotein‐mediateD Drug Transport Journal of Pharmaceutical Sciences. ,vol. 96, pp. 1609- 1618 ,(2007) , 10.1002/JPS.20787
Sanjay U. C. Sankatsing, Jos H. Beijnen, Alfred H. Schinkel, Joep M. A. Lange, Jan M. Prins, P glycoprotein in human immunodeficiency virus type 1 infection and therapy Antimicrobial Agents and Chemotherapy. ,vol. 48, pp. 1073- 1081 ,(2004) , 10.1128/AAC.48.4.1073-1081.2004
X. Deng, S. E. StJohn, H. L. Osswald, A. O'Brien, B. S. Banach, K. Sleeman, A. K. Ghosh, A. D. Mesecar, S. C. Baker, Coronaviruses Resistant to a 3C-Like Protease Inhibitor Are Attenuated for Replication and Pathogenesis, Revealing a Low Genetic Barrier but High Fitness Cost of Resistance Journal of Virology. ,vol. 88, pp. 11886- 11898 ,(2014) , 10.1128/JVI.01528-14
Dirk Daelemans, Rudi Pauwels, Erik De Clercq, Christophe Pannecouque, A time-of-drug addition approach to target identification of antiviral compounds Nature Protocols. ,vol. 6, pp. 925- 933 ,(2011) , 10.1038/NPROT.2011.330
Himani Kukreti Himani Kukreti, PK Dash, Manmohan Parida Manmohan Parida, Artee Chaudhary Artee Chaudhary, Parag Saxena Parag Saxena, RS Rautela, Veena Mittal Veena Mittal, Mala Chhabra Mala Chhabra, D Bhattacharya, Shiv Lal Shiv Lal, PVL Rao, Arvind Rai Arvind Rai, Phylogenetic studies reveal existence of multiple lineages of a single genotype of DENV-1 (genotype III) in India during 1956–2007 Virology Journal. ,vol. 6, pp. 1- 9 ,(2009) , 10.1186/1743-422X-6-1
Y. Kim, S. Lovell, K.-C. Tiew, S. R. Mandadapu, K. R. Alliston, K. P. Battaile, W. C. Groutas, K.-O. Chang, Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses Journal of Virology. ,vol. 86, pp. 11754- 11762 ,(2012) , 10.1128/JVI.01348-12