Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors
Copyright © 2024 Elsevier B.V. All rights reserved..
The main protease (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like protease and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic cysteine and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:225 |
|---|---|
| Enthalten in: |
Antiviral research - 225(2024) vom: 01. Apr., Seite 105874 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Khatua, Kaustav [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 19.04.2024 Date Revised 19.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.antiviral.2024.105874 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370445473 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370445473 | ||
| 003 | DE-627 | ||
| 005 | 20240419232548.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240331s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.antiviral.2024.105874 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1380.xml |
| 035 | |a (DE-627)NLM370445473 | ||
| 035 | |a (NLM)38555023 | ||
| 035 | |a (PII)S0166-3542(24)00083-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Khatua, Kaustav |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors |
| 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 19.04.2024 | ||
| 500 | |a Date Revised 19.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier B.V. All rights reserved. | ||
| 520 | |a The main protease (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like protease and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic cysteine and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Azapeptide | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Covalent inhibitor | |
| 650 | 4 | |a Main protease | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 7 | |a 3C-like proteinase, SARS-CoV-2 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Cysteine |2 NLM | |
| 650 | 7 | |a K848JZ4886 |2 NLM | |
| 650 | 7 | |a Cysteine Endopeptidases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Viral Nonstructural Proteins |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Coronavirus 3C Proteases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.28 |2 NLM | |
| 700 | 1 | |a Alugubelli, Yugendar R |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Kai S |e verfasserin |4 aut | |
| 700 | 1 | |a Vulupala, Veerabhadra R |e verfasserin |4 aut | |
| 700 | 1 | |a Blankenship, Lauren R |e verfasserin |4 aut | |
| 700 | 1 | |a Coleman, Demonta |e verfasserin |4 aut | |
| 700 | 1 | |a Atla, Sandeep |e verfasserin |4 aut | |
| 700 | 1 | |a Chaki, Sankar P |e verfasserin |4 aut | |
| 700 | 1 | |a Geng, Zhi Zachary |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Xinyu R |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Peng-Hsun |e verfasserin |4 aut | |
| 700 | 1 | |a Cho, Chia-Chuan D |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Shivangi |e verfasserin |4 aut | |
| 700 | 1 | |a Vatansever, Erol C |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yuying |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Ge |e verfasserin |4 aut | |
| 700 | 1 | |a Neuman, Benjamin W |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Shiqing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wenshe Ray |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Antiviral research |d 1983 |g 225(2024) vom: 01. Apr., Seite 105874 |w (DE-627)NLM012601756 |x 1872-9096 |7 nnns |
| 773 | 1 | 8 | |g volume:225 |g year:2024 |g day:01 |g month:04 |g pages:105874 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.antiviral.2024.105874 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 225 |j 2024 |b 01 |c 04 |h 105874 | ||