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FEBS Open Bio ; 12:287, 2022.
Article in English | EMBASE | ID: covidwho-1976659


The global pandemic prompted by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has already caused more than 6 million deaths worldwide, calling for urgent effective therapeutic measures. A deep understanding of the mechanisms involved in viral replication is required. Among the nonstructural proteins (nsps) encoded by SARS-CoV-2 genome, there is the nsp14 ribonuclease, the main object of study in this work. Ribonucleases are key factors in the control of all biological processes, ensuring maturation, degradation, and quality control of all types of RNAs. Nsp14 is a bifunctional protein, holding a 3'- 5' exoribonucleolytic activity (ExoN) in the N-terminal domain, stimulated through the interaction with nsp10, and a C-terminal N7-methyltransferase activity (MTase). Both are critical for the coronavirus life cycle. In this work, we provide a complete biochemical characterization of SARS-CoV-2 nsp14-nsp10, addressing several aspects of the complex for the first time. Moreover, using a homology model, we have identified residues involved in the nsp14-nsp10 interaction that were extensively studied. We have confirmed the SARS-CoV-2 nsp14 dual function and we have shown that both ExoN and MTase activities are functionally independent. We demonstrate that the nsp14 MTase activity is independent of nsp10, contrarily to nsp14 ExoN that is upregulated in the presence of the cofactor. Additionally, our results show that the ExoN motif I has a prominent role on the ribonucleolytic activity of SARS-CoV-2 nsp14, contrasting to what was previously observed in other coronaviruses, which can be related to the pathogenesis of SARS-CoV-2. The knowledge provided in this work can serve as a basis to design effective drugs that target the pinpointed residues in order to disturb the complex assembly and affect the viral replication, ultimately, treating COVID-19 and other CoV infections.

FEBS Open Bio ; 12:286-287, 2022.
Article in English | EMBASE | ID: covidwho-1976637


Coronaviruses have emerged as important agents of human infection. SARS-CoV-2, the causative agent of COVID-19, has triggered a global pandemic with devastating consequences. The understanding of fundamental aspects of these viruses is of extreme importance. Fast vaccine development has been a crucial factor in preventing serious disease, but the fast-paced emergence of new variants raises many problems. Viral non-structural proteins are fundamental for viral replication. SARS-CoV-2 nsp16 is a 20-O-methyltransferase with a pivotal role in Interferon antagonism. Nsp16 methylates viral RNA to mimic the host mRNA and then the cell stops recognizing it as foreign. This activity is stimulated by the interaction with nsp10. This protein also acts as a co-factor for the exoribonucleolytic activity of nsp14. Nsp14 also has significant anti-interferon importance that stems from its 2 distinct activities: the N-terminal 3'-to-5' exoribonuclease (ExoN) and a C-terminal N7-methyltransferase (N7-MTase). Unlike Spike proteins, these nsp10, nsp14, and nsp16 are highly conserved among viral variants. In this work, we are studying them and finding inhibitors in order to develop new therapies. Nsp10 is the prime target of our focus since it is the central player in the regulation of both nsp14 and nsp16.