Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L
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 IC 50 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 and two lead analogues potently inhibit SARS-CoV-2 infection in vitro , with EC 50 values in the nanomolar range, thus further highlighting the potential of cathepsin L as a COVID-19 antiviral drug target.
| Errataetall: |
UpdateIn: J Med Chem. 2022 Feb 24;65(4):2956-2970. - PMID 34730959 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2020 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2020) vom: 24. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ashhurst, Anneliese S [VerfasserIn] |
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Date Revised 03.11.2022 published: Electronic UpdateIn: J Med Chem. 2022 Feb 24;65(4):2956-2970. - PMID 34730959 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2020.12.23.424111 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM319621839 |
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| 500 | |a UpdateIn: J Med Chem. 2022 Feb 24;65(4):2956-2970. - PMID 34730959 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 IC 50 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 and two lead analogues potently inhibit SARS-CoV-2 infection in vitro , with EC 50 values in the nanomolar range, thus further highlighting the potential of cathepsin L as a COVID-19 antiviral drug target | ||
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| 700 | 1 | |a Tang, Arthur H |e verfasserin |4 aut | |
| 700 | 1 | |a Fajtová, Pavla |e verfasserin |4 aut | |
| 700 | 1 | |a Yoon, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Aggarwal, Anupriya |e verfasserin |4 aut | |
| 700 | 1 | |a Stoye, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Larance, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Beretta, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Drelich, Aleksandra |e verfasserin |4 aut | |
| 700 | 1 | |a Skinner, Danielle |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Linfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Meek, Thomas D |e verfasserin |4 aut | |
| 700 | 1 | |a McKerrow, James H |e verfasserin |4 aut | |
| 700 | 1 | |a Hook, Vivian |e verfasserin |4 aut | |
| 700 | 1 | |a Tseng, Chien-Te K |e verfasserin |4 aut | |
| 700 | 1 | |a Turville, Stuart |e verfasserin |4 aut | |
| 700 | 1 | |a Gerwick, William H |e verfasserin |4 aut | |
| 700 | 1 | |a O'Donoghue, Anthony J |e verfasserin |4 aut | |
| 700 | 1 | |a Payne, Richard J |e verfasserin |4 aut | |
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