PXD054356-1

PXD054356 is an original dataset announced via ProteomeXchange.

Title	PLpro inhibition protects in post-acute sequelae mouse model of COVID-19
Description	The COVID-19 pandemic has highlighted how vulnerable a globally connected population is to the threat of newly emerging zoonotic viruses, exemplified by SARS-CoV-2. Despite considerable efforts to identify antivirals for coronaviruses (CoVs) in the last two decades, there exists only one FDA-approved, effective drug, Paxlovid which targets the essential SARS-CoV-2 main protease. Whilst effective in the acute phase of the pandemic, Paxlovid cannot be used by all patients, can lead to viral recurrence, and has not demonstrated an effect on post-acute sequelae of COVID-19 (PASC), commonly known as Long COVID, an emerging significant health burden that remains poorly understood and untreated. Alternative orthogonal antivirals that are addressing broader patient needs, are urgently required. Herein we report our drug discovery efforts targeting PLpro, the second essential coronaviral protease, for which we have identified and developed a novel chemical scaffold that targets SARS-CoV-2 with low nanomolar activity. This chemical class also exhibits broad-spectrum activity against other pathogenic coronavirus PLpros. Our lead compound shows in vivo efficacy superior to Paxlovid in a mouse model of severe disease. Importantly, our mouse model of severe infection leads to long term pathologies matching closely those seen in PASC patients, including lung, heart, brain and gut dysfunctions. We show that our lead compound protects against long term lung and brain dysfunction in this model, whereas Paxlovid does not, providing a potential treatment option for PASC sufferers going forward.
HostingRepository	PRIDE
AnnounceDate	2025-02-23
AnnouncementXML	Submission_2025-02-22_20:22:35.821.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Maria Tanzer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-29 18:14:16	ID requested
⏵ 1	2025-02-22 20:22:36	announced

Dataset with its publication pending

submitter keyword: SARS-CoV-2

Long COVID

PASC

Inflammation

David Komander
contact affiliation	Head, Ubiquitin Signalling Division The Walter and Eliza Hall Institute of Medical Research 1G Royal Parade, Parkville 3052, VIC, Australia Professor, Department of Medical Biology University of Melbourne, 3010 Melbourne, VIC, Australia
contact email	dk@wehi.edu.au
lab head
Maria Tanzer
contact affiliation	Walter and Eliza Hall Institute
contact email	tanzer@wehi.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054356
     1. Label: PRIDE project
     2. Name: PLpro inhibition protects in post-acute sequelae mouse model of COVID-19