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.
Highlights
Published: 1 February 2022Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 in Wuhan, China [1] and rapidly spread worldwide, initiating a global pandemic
A profound knowledge of the mechanisms involved in viral replication is of the utmost urgency and will surely contribute to the development of new treatments against COVID-19, the disease caused by SARS-CoV-2
Our results show that this endoribonuclease is able to cleave this substrate (Figure 2C, right panel), confirming that SARS-CoV-2 nsp15 can cleave both ss and dsRNA molecules
Summary
Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 in Wuhan, China [1] and rapidly spread worldwide, initiating a global pandemic. The catalytic site at the NendoU domain is composed of the highly conserved residues H235, H250 and K290 (numbering according to the SARS-CoV-2 PDB 6VWW [17]) (Figure 1D) that constitute the catalytic triad, similar to what was described for bovine RNase A [21]. This suggests a similar mechanism of action, but while RNase A does not require a cofactor, nsp activity is stimulated by. We performed an in silico screening to find the best commercially available and approved drugs that might inhibit the NendoU activity of nsp
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
