The Swiss army knife of SARS-CoV-2: the structures and functions of NSP3

Soosten, Lea C. von; Edich, Maximilian; Nolte, Kristopher; Kaub, Johannes; Santoni, Gianluca; Thorn, Andrea

doi:10.1080/0889311x.2022.2098281

Cited by 5 publications

(3 citation statements)

References 40 publications

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“…As an NSP12 cofactor, NSP7 was also included in the study, but mutations were absent in the respective aminoacidic sequence. We found nine mutations in the NSP3 sequence [34] (Figure 3A,B), specifically T73I and T86I in the ubiquitin-like domain 1 (Ubl-1), E134G in the Glu-rich acidic region (AC domain), A488S in the SARS-unique domain (SUD), Y1185N in the nucleic-acid-binding domain (NAB domain), P1228L in the Betacoronavirus-specific marker domain (G2M domain), and, finally, Y1463H, P1469S, and We identified three mutations on NSP12 [38] (Figure 5A,B): V42A in the β-hairpin region, P323L on the interface domain, and G671S on the fingers' subdomain. In addition, two mutations were found at the C-terminal domain of its cofactor NSP8: R111A and T145I.…”

Section: Structural Analysismentioning

confidence: 89%

COVID-19 Genomic Surveillance in Bangui (Central African Republic) Reveals a Landscape of Circulating Variants Linked to Validated Antiviral Targets of SARS-CoV-2 Proteome

Vickos,

Camasta,

Grandi

et al. 2023

Viruses

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Since its outbreak, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spread rapidly, causing the Coronavirus Disease 19 (COVID-19) pandemic. Even with the vaccines’ administration, the virus continued to circulate due to inequal access to prevention and therapeutic measures in African countries. Information about COVID-19 in Africa has been limited and contradictory, and thus regional studies are important. On this premise, we conducted a genomic surveillance study about COVID-19 lineages circulating in Bangui, Central African Republic (CAR). We collected 2687 nasopharyngeal samples at four checkpoints in Bangui from 2 to 22 July 2021. Fifty-three samples tested positive for SARS-CoV-2, and viral genomes were sequenced to look for the presence of different viral strains. We performed phylogenetic analysis and described the lineage landscape of SARS-CoV-2 circulating in the CAR along 15 months of pandemics and in Africa during the study period, finding the Delta variant as the predominant Variant of Concern (VoC). The deduced aminoacidic sequences of structural and non-structural genes were determined and compared to reference and reported isolates from Africa. Despite the limited number of positive samples obtained, this study provides valuable information about COVID-19 evolution at the regional level and allows for a better understanding of SARS-CoV-2 circulation in the CAR.

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Section: Structural Analysismentioning

confidence: 89%

COVID-19 Genomic Surveillance in Bangui (Central African Republic) Reveals a Landscape of Circulating Variants Linked to Validated Antiviral Targets of SARS-CoV-2 Proteome

Vickos,

Camasta,

Grandi

et al. 2023

Viruses

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“…Nsp3 is a 1945 amino acid protein that consists of 14 domains: ubiquitin-like 1 domain (Ubl-1), Acidic domain (Ac), X domain (X), SARS-unique domain (SUD), ubiquitin-like 2 domain (Ubl-2), Papain-Like 2 protease domain (PL2pro), Nucleic acid-binding domain (NAB), betacoronavirus-specific marker domain (βSM), transmembrane domain 1 (TM1), nsp3 ectodomain (3Ecto), transmembrane domain 2 (TM2), Amphipathic helix 1 domain (AH1), Y1 domain (Y1), and CoV-Y domain (CoV-Y) ( 35 – 37 ). It is the longest protein encoded in coronaviruses.…”

Section: Nsp3mentioning

confidence: 99%

What do we know about the function of SARS-CoV-2 proteins?

Justo Arevalo,

Castillo-Chávez,

Uribe Calampa

et al. 2023

Front. Immunol.

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The COVID-19 pandemic has highlighted the importance in the understanding of the biology of SARS-CoV-2. After more than two years since the first report of COVID-19, it remains crucial to continue studying how SARS-CoV-2 proteins interact with the host metabolism to cause COVID-19. In this review, we summarize the findings regarding the functions of the 16 non-structural, 6 accessory and 4 structural SARS-CoV-2 proteins. We place less emphasis on the spike protein, which has been the subject of several recent reviews. Furthermore, comprehensive reviews about COVID-19 therapeutic have been also published. Therefore, we do not delve into details on these topics; instead we direct the readers to those other reviews. To avoid confusions with what we know about proteins from other coronaviruses, we exclusively report findings that have been experimentally confirmed in SARS-CoV-2. We have identified host mechanisms that appear to be the primary targets of SARS-CoV-2 proteins, including gene expression and immune response pathways such as ribosome translation, JAK/STAT, RIG-1/MDA5 and NF-kβ pathways. Additionally, we emphasize the multiple functions exhibited by SARS-CoV-2 proteins, along with the limited information available for some of these proteins. Our aim with this review is to assist researchers and contribute to the ongoing comprehension of SARS-CoV-2’s pathogenesis.

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“…SARS-CoV and SARS-CoV-2 PLpro show an overall 83% sequence identity, being highly conserved within the coronavirus family [PMCID: PMC7430346], and raising the possibility of development of a broad spectrum anti-coronaviridae inhibitors [4]. Nsp3 is composed of five domains, named from nsp3a to 3e, connected through different linkers and followed by two transmembrane regions (TM) and a Y-domain at the C-term [5]. The proteolytically active papain-like protease domain (PLpro) is part of the nsp3d region.…”

Section: Introductionmentioning

confidence: 99%

Resolving the pharmacological redox-sensitivity of SARS-CoV-2 PLpro in drug repurposing screening enabled identification of the competitive GRL-0617 binding site inhibitor CPI-169

Kuzikov,

Morasso,

Reinshagen

et al. 2023

Preprint

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The SARS CoV-2 Papain-Like protease has multiple roles in the viral replication cycle, related to both its polypeptide cleavage function and its capacity to antagonize host immune response. Targeting PLpro function is recognized as a promising mechanism to modulate viral replication whilst supporting host immune responses. However, development of PLpro specific inhibitors remains challenging. Upcoming studies revealed the limitation of reported inhibitors by profiling them through a pipeline of enzymatic, binding and cellular activity assays showing unspecific activity. GRL-0617 remained the only validated molecule with demonstrated anti-viral activity in cells. In this study we refer to the pitfalls of redox-sensitivity of PLpro. Using a screening-based approach to identify inhibitors of PLpro proteolytic activity, we made extensive efforts to validate the active compounds over a range of conditions and readouts, emphasising the need for comprehensive orthogonal data when profiling putative PLpro inhibitors. The remaining active compound CPI-169, showed to compete with GRL-0617 in NMR-based experiments, suggesting to share a similar binding mode, opening novel design opportunities for further developments as antiviral agents.

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The Swiss army knife of SARS-CoV-2: the structures and functions of NSP3

Cited by 5 publications

References 40 publications

COVID-19 Genomic Surveillance in Bangui (Central African Republic) Reveals a Landscape of Circulating Variants Linked to Validated Antiviral Targets of SARS-CoV-2 Proteome

COVID-19 Genomic Surveillance in Bangui (Central African Republic) Reveals a Landscape of Circulating Variants Linked to Validated Antiviral Targets of SARS-CoV-2 Proteome

What do we know about the function of SARS-CoV-2 proteins?

Resolving the pharmacological redox-sensitivity of SARS-CoV-2 PLpro in drug repurposing screening enabled identification of the competitive GRL-0617 binding site inhibitor CPI-169

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