Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2
© 2024 The Authors. Published by American Chemical Society..
The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (HsDHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated naphthoquinone fragments, discovering potent HsDHODH inhibition with IC50 ranging from 48 to 684 nM, and promising in vitro anti-SARS-CoV-2 activity with EC50 ranging from 1.2 to 2.3 μM. These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools such as molecular docking and quantitative structure-activity relationship (QSAR) models to analyze protein-ligand interactions, revealing that these naphthoquinones exhibit a protein binding pattern similar to brequinar, a potent HsDHODH inhibitor. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
|---|---|
| Enthalten in: |
ACS omega - 9(2024), 10 vom: 12. März, Seite 11418-11430 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Purificação, Aline D [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 19.03.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1021/acsomega.3c07845 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36986638X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36986638X | ||
| 003 | DE-627 | ||
| 005 | 20240319233319.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240318s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acsomega.3c07845 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1336.xml |
| 035 | |a (DE-627)NLM36986638X | ||
| 035 | |a (NLM)38496952 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Purificação, Aline D |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2 |
| 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 Revised 19.03.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2024 The Authors. Published by American Chemical Society. | ||
| 520 | |a The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (HsDHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated naphthoquinone fragments, discovering potent HsDHODH inhibition with IC50 ranging from 48 to 684 nM, and promising in vitro anti-SARS-CoV-2 activity with EC50 ranging from 1.2 to 2.3 μM. These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools such as molecular docking and quantitative structure-activity relationship (QSAR) models to analyze protein-ligand interactions, revealing that these naphthoquinones exhibit a protein binding pattern similar to brequinar, a potent HsDHODH inhibitor. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Silva-Mendonça, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz, Luiza V |e verfasserin |4 aut | |
| 700 | 1 | |a Sacramento, Carolina Q |e verfasserin |4 aut | |
| 700 | 1 | |a Temerozo, Jairo R |e verfasserin |4 aut | |
| 700 | 1 | |a Fintelman-Rodrigues, Natalia |e verfasserin |4 aut | |
| 700 | 1 | |a de Freitas, Caroline Souza |e verfasserin |4 aut | |
| 700 | 1 | |a Godoi, Bruna Fleck |e verfasserin |4 aut | |
| 700 | 1 | |a Vaidergorn, Miguel Menezes |e verfasserin |4 aut | |
| 700 | 1 | |a Leite, Juliana Almeida |e verfasserin |4 aut | |
| 700 | 1 | |a Salazar Alvarez, Luis Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Freitas, Murillo V |e verfasserin |4 aut | |
| 700 | 1 | |a Silvac, Meryck F B |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Bianca A |e verfasserin |4 aut | |
| 700 | 1 | |a Lopez, Renata F V |e verfasserin |4 aut | |
| 700 | 1 | |a Neves, Bruno J |e verfasserin |4 aut | |
| 700 | 1 | |a Costa, Fabio T M |e verfasserin |4 aut | |
| 700 | 1 | |a Souza, Thiago M L |e verfasserin |4 aut | |
| 700 | 1 | |a da Silva Emery, Flavio |e verfasserin |4 aut | |
| 700 | 1 | |a Andrade, Carolina Horta |e verfasserin |4 aut | |
| 700 | 1 | |a Nonato, M Cristina |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ACS omega |d 2016 |g 9(2024), 10 vom: 12. März, Seite 11418-11430 |w (DE-627)NLM264243048 |x 2470-1343 |7 nnns |
| 773 | 1 | 8 | |g volume:9 |g year:2024 |g number:10 |g day:12 |g month:03 |g pages:11418-11430 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acsomega.3c07845 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 9 |j 2024 |e 10 |b 12 |c 03 |h 11418-11430 | ||