Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2

Author(s):Show less -

Purificacao, Aline D. ; Silva-Mendonca, Sabrina ; Cruz, Luiza V. ; Sacramento, Carolina Q. ; Temerozo, Jairo R. ; Fintelman-Rodrigues, Natalia ; de Freitas, Caroline Souza ; Godoi, Bruna Fleck ; Vaidergorn, Miguel Menezes ; Leite, Juliana Almeida ; Alvarez, Luis Carlos Salazar ; Freitas, Murillo V. ; Silvac, Meryck F. B. ; Martin, Bianca A. ; Lopez, Renata F. V. ; Neves, Bruno J. ; Costa, Fabio T. M. ; Souza, Thiago M. L. ; Emery, Flavio da Silva ; Andrade, Carolina Horta ; Nonato, M. Cristina

• Document type: Journal article
• Source: ACS OMEGA; v. 9, n. 10, p. 13-pg., 2024-02-28.

Abstract

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 mu M. 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. (AU)

• FAPESP's process: 20/05369-6 - Artificial inteligence driven drug repositioning strategy for COVID-19
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/10084-3 - Development of covalent inhibitors of the enzyme dihydroorotate dehydrogenase for the discovery of therapeutic candidates for Chagas disease
• Grantee: Bruna Fleck Godoi
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/06190-0 - Drug repurposing and search of selective inhibitors for human dihydroorotate dehydrogenase as a strategy in fighting against COVID-19
• Grantee: Maria Cristina Nonato
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/13237-5 - Search for Human Dihydroorotate Dehydrogenase inhibitors as a new strategy against COVID-19 disease
• Grantee: Aline Dias da Purificação
• Support Opportunities: Scholarships in Brazil - Master