The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: Mechanism of Action and Its Inactivation with FDA-Approved Drugs

Saramago, Margarida; Costa, Vanessa G.; Souza, Caio S.; Bárria, Cátia; Domingues, Susana; Viegas, Sandra C.; Lousa, Diana; Soares, Cláudio M.; Arraiano, Cecília M.; Matos, Rute G.

doi:10.3390/microorganisms10020342

Open AccessEditor’s ChoiceArticle

The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: Mechanism of Action and Its Inactivation with FDA-Approved Drugs

by

Margarida Saramago

^*,†

,

Vanessa G. Costa

^†,

Caio S. Souza

,

Cátia Bárria

,

Susana Domingues

,

Sandra C. Viegas

,

Diana Lousa

,

Cláudio M. Soares

,

Cecília M. Arraiano

^* and

Rute G. Matos

^*

Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Avenida da Republica, 2780-157 Oeiras, Portugal

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Microorganisms 2022, 10(2), 342; https://doi.org/10.3390/microorganisms10020342

Submission received: 16 December 2021 / Revised: 14 January 2022 / Accepted: 20 January 2022 / Published: 1 February 2022

(This article belongs to the Special Issue Advances in RNA Biology in Pathogenic Microorganisms)

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Abstract

The pandemic caused by SARS-CoV-2 is not over yet, despite all the efforts from the scientific community. Vaccination is a crucial weapon to fight this virus; however, we still urge the development of antivirals to reduce the severity and progression of the COVID-19 disease. For that, a deep understanding of the mechanisms involved in viral replication is necessary. nsp15 is an endoribonuclease critical for the degradation of viral polyuridine sequences that activate host immune sensors. This enzyme is known as one of the major interferon antagonists from SARS-CoV-2. In this work, a biochemical characterization of SARS-CoV-2 nsp15 was performed. We saw that nsp15 is active as a hexamer, and zinc can block its activity. The role of conserved residues from SARS-CoV-2 nsp15 was investigated, and N164 was found to be important for protein hexamerization and to contribute to the specificity to degrade uridines. Several chemical groups that impact the activity of this ribonuclease were also identified. Additionally, FDA-approved drugs with the capacity to inhibit the in vitro activity of nsp15 are reported in this work. This study is of utmost importance by adding highly valuable information that can be used for the development and rational design of therapeutic strategies.

Keywords: SARS-CoV-2; ribonucleases; nsp15; inhibitors; FDA-approved compounds; therapeutics

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MDPI and ACS Style

Saramago, M.; Costa, V.G.; Souza, C.S.; Bárria, C.; Domingues, S.; Viegas, S.C.; Lousa, D.; Soares, C.M.; Arraiano, C.M.; Matos, R.G. The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: Mechanism of Action and Its Inactivation with FDA-Approved Drugs. Microorganisms 2022, 10, 342. https://doi.org/10.3390/microorganisms10020342

AMA Style

Saramago M, Costa VG, Souza CS, Bárria C, Domingues S, Viegas SC, Lousa D, Soares CM, Arraiano CM, Matos RG. The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: Mechanism of Action and Its Inactivation with FDA-Approved Drugs. Microorganisms. 2022; 10(2):342. https://doi.org/10.3390/microorganisms10020342

Chicago/Turabian Style

Saramago, Margarida, Vanessa G. Costa, Caio S. Souza, Cátia Bárria, Susana Domingues, Sandra C. Viegas, Diana Lousa, Cláudio M. Soares, Cecília M. Arraiano, and Rute G. Matos. 2022. "The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: Mechanism of Action and Its Inactivation with FDA-Approved Drugs" Microorganisms 10, no. 2: 342. https://doi.org/10.3390/microorganisms10020342

APA Style

Saramago, M., Costa, V. G., Souza, C. S., Bárria, C., Domingues, S., Viegas, S. C., Lousa, D., Soares, C. M., Arraiano, C. M., & Matos, R. G. (2022). The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: Mechanism of Action and Its Inactivation with FDA-Approved Drugs. Microorganisms, 10(2), 342. https://doi.org/10.3390/microorganisms10020342

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The nsp15 Nuclease as a Good Target to Combat SARS-CoV-2: Mechanism of Action and Its Inactivation with FDA-Approved Drugs

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