@article{00ad7b56ff834e25aa491f77ce213919,
title = "Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors",
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 antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, 5c and 3k, originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as in vitro absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor 3k guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an in vitro SARS-CoV-2 infection model, justifying further optimization.",
keywords = "ADME, COVID-19, inhibitor, Nsp3, PLpro, repurposing, SARS-CoV-2, structure",
author = "Calleja, {Dale J.} and Nathan Kuchel and Lu, {Bernadine G.C.} and Birkinshaw, {Richard W.} and Theresa Klemm and Marcel Doerflinger and Cooney, {James P.} and Liana Mackiewicz and Au, {Amanda E.} and Yap, {Yu Q.} and Blackmore, {Timothy R.} and Kasiram Katneni and Elly Crighton and Janet Newman and Jarman, {Kate E.} and Call, {Melissa J.} and Lechtenberg, {Bernhard C.} and Czabotar, {Peter E.} and Marc Pellegrini and Charman, {Susan A.} and Lowes, {Kym N.} and Mitchell, {Jeffrey P.} and Ueli Nachbur and Guillaume Lessene and David Komander",
note = "Funding Information: 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. Funding Information: 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{\textquoteright}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{\textquoteright}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. Publisher Copyright: Copyright {\textcopyright} 2022 Calleja, Kuchel, Lu, Birkinshaw, Klemm, Doerflinger, Cooney, Mackiewicz, Au, Yap, Blackmore, Katneni, Crighton, Newman, Jarman, Call, Lechtenberg, Czabotar, Pellegrini, Charman, Lowes, Mitchell, Nachbur, Lessene and Komander.",
year = "2022",
month = apr,
day = "12",
doi = "10.3389/fchem.2022.861209",
language = "English",
volume = "10",
journal = "Frontiers in Chemistry",
issn = "2296-2646",
publisher = "Frontiers Media SA",
}