Journal article
Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors
DJ Calleja, N Kuchel, BGC Lu, RW Birkinshaw, T Klemm, M Doerflinger, JP Cooney, L Mackiewicz, AE Au, YQ Yap, TR Blackmore, K Katneni, E Crighton, J Newman, KE Jarman, MJ Call, BC Lechtenberg, PE Czabotar, M Pellegrini, SA Charman Show all
Frontiers in Chemistry | Published : 2022
Abstract
The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivir..
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Awarded by Australian War Memorial
Funding Acknowledgements
This work was funded by The Walter and Eliza Hall Institute of Medical Research, an NHMRC/MRFF "VirDUB" grant MRF2002119 (to DK, GL, MP, and PC), NHMRC Investigator Grants and Fellowships (GNT1178122 to DK, GNT0637350 to MP, and GNT1117089 to GL), a Wellcome Trust Grant (WT222698/Z/21/Z to DK, GL, and MP), NHMRC Independent Research Institutes Infrastructure Support Scheme grant (361646) and Victorian State Government Operational Infrastructure Support grant, and a generous donation by Hengyi Pacific Pty Ltd to support COVID-19 research. Compound screening was conducted at the Walter and Eliza Hall Institute's National Drug Discovery Centre (NDDC). The NDDC received grant funding from the Australian Government and the Victorian State Government, with additional support from generous philanthropic donors including Mike Fitzpatrick, Helen Sykes and AWM Electrical. WEHI's screening facilities and the Centre for Drug Candidate Optimisation (CDCO, Monash University) are also supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. The CDCO is also supported by the Monash Technology Research Platform network.