PXD027300

PXD027300 is an original dataset announced via ProteomeXchange.

Title	Potent anti-SARS-CoV-2 activity by the natural product gallinamide A and analogues via inhibition of cathepsin L
Description	The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro and PLpro. We demonstrate that gallinamide A directly interacts with cathepsin L in cells, and together with two lead analogues potently inhibits SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. However, in an in vivo mouse model of infection, gallinamide A did not reduce viral load in the lung tissue, possibly due to compensatory viral entry mechanisms. In support of this, in TMPRSS2-overexpressing cells gallinamide A had reduced anti-viral activity, but when combined with a TMPRSS2 inhibitor synergistically improved inhibition of viral entry. The data highlights the potential of cathepsin L as a COVID-19 antiviral drug target, and the likely necessity to inhibit multiple routes of viral entry routes to achieve therapeutic efficacy.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-17_05:19:25.412.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Travis Ruan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-14 07:28:34	ID requested
⏵ 1	2022-02-17 05:19:26	announced

Ashhurst AS, Tang AH, Fajtov, á P, Yoon MC, Aggarwal A, Bedding MJ, Stoye A, Beretta L, Pwee D, Drelich A, Skinner D, Li L, Meek TD, McKerrow JH, Hook V, Tseng CT, Larance M, Turville S, Gerwick WH, O'Donoghue AJ, Payne RJ, Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L. J Med Chem, 65(4):2956-2970(2022) [pubmed]

submitter keyword: SARS-CoV-2, gallinamide A, cathepsin L, COVID, HEK293, MRC5, VEROE6

Mark Larance
contact affiliation	The University of Sydney
contact email	mark.larance@sydney.edu.au
lab head
Travis Ruan
contact affiliation	The University of Sydney
contact email	Travis.Ruan@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027300
     1. Label: PRIDE project
     2. Name: Potent anti-SARS-CoV-2 activity by the natural product gallinamide A and analogues via inhibition of cathepsin L