Allosteric Inhibitors of the SARS-COV-2 Papain-like Protease Domain Induce Proteasomal Degradation of Its Parent Protein NSP3
The papain-like protease of SARS-COV-2 is essential for viral replication and pathogenesis. Its location within a much larger multifunctional protein, NSP3, makes it an ideal candidate for a targeted degradation approach capable of eliminating multiple functions with a single-molecule treatment. In this work, we have developed a HiBiT-based cellular model to study NSP3 degradation and used this platform for the discovery of monovalent NSP3 degraders. We present previously unreported degradation activity of published papain-like protease inhibitors. Follow-up exploration of structure-activity relationships and mechanism-of-action studies points to the recruitment of the ubiquitin-proteasome machinery that is solely driven by site occupancy, regardless of molecular features of the ligand. Supported by HDX data, we hypothesize that binding-induced structural changes in NSP3 trigger the recruitment of an E3 ligase and lead to proteasomal degradation.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
|---|---|
| Enthalten in: |
ACS chemical biology - 19(2024), 1 vom: 19. Jan., Seite 22-36 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Cockram, Peter E [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Coronavirus Papain-Like Proteases |
|---|
| Anmerkungen: |
Date Completed 22.01.2024 Date Revised 22.01.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acschembio.3c00312 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366412329 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366412329 | ||
| 003 | DE-627 | ||
| 005 | 20240122232019.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acschembio.3c00312 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1267.xml |
| 035 | |a (DE-627)NLM366412329 | ||
| 035 | |a (NLM)38150587 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Cockram, Peter E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Allosteric Inhibitors of the SARS-COV-2 Papain-like Protease Domain Induce Proteasomal Degradation of Its Parent Protein NSP3 |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 22.01.2024 | ||
| 500 | |a Date Revised 22.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The papain-like protease of SARS-COV-2 is essential for viral replication and pathogenesis. Its location within a much larger multifunctional protein, NSP3, makes it an ideal candidate for a targeted degradation approach capable of eliminating multiple functions with a single-molecule treatment. In this work, we have developed a HiBiT-based cellular model to study NSP3 degradation and used this platform for the discovery of monovalent NSP3 degraders. We present previously unreported degradation activity of published papain-like protease inhibitors. Follow-up exploration of structure-activity relationships and mechanism-of-action studies points to the recruitment of the ubiquitin-proteasome machinery that is solely driven by site occupancy, regardless of molecular features of the ligand. Supported by HDX data, we hypothesize that binding-induced structural changes in NSP3 trigger the recruitment of an E3 ligase and lead to proteasomal degradation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Papain |2 NLM | |
| 650 | 7 | |a EC 3.4.22.2 |2 NLM | |
| 650 | 7 | |a papain-like protease, SARS-CoV-2 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.2 |2 NLM | |
| 650 | 7 | |a Viral Nonstructural Proteins |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Coronavirus Papain-Like Proteases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.2 |2 NLM | |
| 700 | 1 | |a Walters, Benjamin T |e verfasserin |4 aut | |
| 700 | 1 | |a Lictao, Aaron |e verfasserin |4 aut | |
| 700 | 1 | |a Shanahan, Frances |e verfasserin |4 aut | |
| 700 | 1 | |a Wertz, Ingrid E |e verfasserin |4 aut | |
| 700 | 1 | |a Foster, Scott A |e verfasserin |4 aut | |
| 700 | 1 | |a Rudolph, Joachim |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ACS chemical biology |d 2006 |g 19(2024), 1 vom: 19. Jan., Seite 22-36 |w (DE-627)NLM167137344 |x 1554-8937 |7 nnns |
| 773 | 1 | 8 | |g volume:19 |g year:2024 |g number:1 |g day:19 |g month:01 |g pages:22-36 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acschembio.3c00312 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 19 |j 2024 |e 1 |b 19 |c 01 |h 22-36 | ||