@article{f644b692bbf4485d83452a374ba29c72,
title = "The nsp15 Nuclease as a Good Target to Combat SARS‐CoV‐2: Mechanism of Action and Its Inactivation with FDA‐Approved Drugs",
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 = "FDA‐approved compounds, Inhibitors, Nsp15, Ribonucleases, SARS‐CoV‐2, Therapeutics",
author = "Margarida Saramago and Costa, {Vanessa G.} and Souza, {Caio S.} and C{\'a}tia B{\'a}rria and Susana Domingues and Viegas, {Sandra C.} and Diana Lousa and Soares, {Cl{\'a}udio M.} and Arraiano, {Cec{\'i}lia M.} and Matos, {Rute G.}",
note = "Funding Information: This work was funded by national funds through FCT?Funda??o para a Ci?ncia e a Tecnologia, I.P., Project MOSTMICRO?ITQB with refs UIDB/04612/2020 and UIDP/04612/2020, Project PTDC/BIA?BQM/28479/2017 to R.G.M and project PTDC/CCI?BIO/28200/2017 to D.L. and R.G.M and was also financed by a FCT contract (ref. CEECIND/02065/2017). S.C.V. was financed by FCT program IF (ref. IF/00217/2015). M.S., S.D. and D.L. were financed by a FCT contract according to DL57/2016: SFRH/BPD/109464/2015, SFRH/BPD/84080/2012 and SFRH/BPD/92537/2013, respectively. V.G.C. was a recipient of a doctoral grant funded by FCT (ref. 2021.05169.BD). C.B. has a contract under the project PTDC/BIA?BQM/28479/2017. C.S.S. was financed by a fellowship under the project ShikiFactory100, grant agreement number 814408, from the European Union?s Horizon 2020 Research and Innovation Program. Funding Information: Funding: This work was funded by national funds through FCT—Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia, I.P., Project MOSTMICRO‐ITQB with refs UIDB/04612/2020 and UIDP/04612/2020, Project PTDC/BIA‐BQM/28479/2017 to R.G.M and project PTDC/CCI‐BIO/28200/2017 to D.L. and R.G.M and was also financed by a FCT contract (ref. CEECIND/02065/2017). S.C.V. was financed by FCT program IF (ref. IF/00217/2015). M.S., S.D. and D.L. were financed by a FCT contract according to DL57/2016: SFRH/BPD/109464/2015, SFRH/BPD/84080/2012 and SFRH/BPD/92537/2013, respec‐ tively. V.G.C. was a recipient of a doctoral grant funded by FCT (ref. 2021.05169.BD). C.B. has a contract under the project PTDC/BIA‐BQM/28479/2017. C.S.S. was financed by a fellowship under the project ShikiFactory100, grant agreement number 814408, from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Program. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2022",
month = feb,
doi = "10.3390/microorganisms10020342",
language = "English",
volume = "10",
journal = "Microorganisms",
issn = "2076-2607",
publisher = "MDPI AG",
number = "2",
}