Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design

Malone, Brandon; Urakova, Nadya; Snijder, Eric J.; Campbell, Elizabeth A.

doi:10.1038/s41580-021-00432-z

Cited by 334 publications

(321 citation statements)

References 184 publications

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“…This rate is similar than other RNA viruses such as seasonal influenza (H1N1, H3N2) with a rate between 0.6-2.0 × 10 −3 /site/year [37]. Coronaviruses encode a unique proofreading activity that is not found in other RNA viruses, this activity is encoded in the N-terminal exoribonuclease domain of nsp14, which together with nsp10 forms an RNA proofreading complex [39]. Furthermore, a recent study indicated that the mutational dynamics of SARS-CoV-2 vary in different regions.…”

Section: Relevant Characteristics Of the Sars-cov-2 Genomementioning

confidence: 55%

Emergence of SARS-CoV-2 Variants in the World: How Could This Happen?

Parra-Lucares

Segura

Rojas

et al. 2022

Life

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The COVID-19 pandemic has had a significant global impact, with more than 280,000,000 people infected and 5,400,000 deaths. The use of personal protective equipment and the anti-SARS-CoV-2 vaccination campaigns have reduced infection and death rates worldwide. However, a recent increase in infection rates has been observed associated with the appearance of SARS-CoV-2 variants, including the more recently described lineage B.1.617.2 (Delta variant) and lineage B.1.1.529/BA.1 (Omicron variant). These new variants put the effectiveness of international vaccination at risk, with the appearance of new outbreaks of COVID-19 throughout the world. This emergence of new variants has been due to multiple predisposing factors, including molecular characteristics of the virus, geographic and environmental conditions, and the impact of social determinants of health that favor the genetic diversification of SARS-CoV-2. We present a literature review on the most recent information available on the emergence of new variants of SARS-CoV-2 in the world. We analyzed the biological, geographical, and sociocultural factors that favor the development of these variants. Finally, we evaluate the surveillance strategies for the early detection of new variants and prevent their distribution outside these regions.

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Section: Relevant Characteristics Of the Sars-cov-2 Genomementioning

confidence: 55%

Emergence of SARS-CoV-2 Variants in the World: How Could This Happen?

Parra-Lucares

Segura

Rojas

et al. 2022

Life

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“…Coronaviruses are a family of large positive sense single stranded (ss) RNA viruses that utilize a multi-subunit replication-transcription complex (RTC) to replicate the viral genome and synthesize sub-genomic viral mRNA transcripts within double membrane vesicles 1,2 . The RTC is composed of multiple viral non-structural proteins (Nsps), including an RNAdependent RNA polymerase (RdRp, Nsp12), RNA helicase (Nsp13), dual exonuclease/N7-Methyltransferase (Nsp14), 2'O-Methyltransferase (Nsp16), and multiple accessory/cofactor subunits (Nsp7, Nsp8, Nsp9 and Nsp10) [2][3][4][5][6] . The RTC is a leading target for new anti-viral therapeutics such as nucleotide analogues that specifically target the Nsp12 polymerase subunit [6][7][8] .…”

Section: Main Textmentioning

confidence: 99%

Flipped Over U: Structural Basis for dsRNA Cleavage by the SARS-CoV-2 Endoribonuclease

Frazier

Wilson

Krahn

et al. 2022

Preprint

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Coronaviruses generate double-stranded (ds) RNA intermediates during viral replication that can activate host immune sensors. To evade activation of the host pattern recognition receptor MDA5, coronaviruses employ Nsp15, which is uridine-specific endoribonuclease. Nsp15 is proposed to associate with the coronavirus replication-transcription complex within double-membrane vesicles to cleave these dsRNA intermediates. How Nsp15 recognizes and processes dsRNA is poorly understood because previous structural studies of Nsp15 have been limited to small single-stranded (ss) RNA substrates. Here we present cryo-EM structures of SARS-CoV-2 Nsp15 bound to a 52nt dsRNA. We observed that the Nsp15 hexamer forms a platform for engaging dsRNA across multiple protomers. The structures, along with site-directed mutagenesis and RNA cleavage assays revealed critical insight into dsRNA recognition and processing. To process dsRNA Nsp15 utilizes a base-flipping mechanism to properly orient the uridine within the active site for cleavage. Our findings show that Nsp15 is a distinctive endoribonuclease that can cleave both ss- and dsRNA effectively.

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“…SARS-CoV-2 is an enveloped, positive sense, single-stranded RNA virus ( Kim et al, 2020 , Malone et al, 2022 ). The SARS-CoV-2 proteins consist of two large polyproteins named ORF1a and ORF1b (ORFs are proteolytically cleaved into 16 functional non-structural proteins (NSPs) ( Rohaim et al, 2021 )), four structural proteins (Envelope (E), Membrane (M), Nucleocapsid (N) spike (S) proteins)) and accessory proteins ( Kim et al, 2020 , Wu et al, 2020b ).…”

Section: Introductionmentioning

confidence: 99%

Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19 -associated main enzymes

Alıcı

Tahtacı

Demır

2022

Computational Biology and Chemistry

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Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design

Abstract: RNA genome of positive polarityAn RNA genome that has mRNA polarity and, when released from viral particles, can be used directly by host ribosomes to produce viral proteins.

Cited by 334 publications

References 184 publications

Emergence of SARS-CoV-2 Variants in the World: How Could This Happen?

Emergence of SARS-CoV-2 Variants in the World: How Could This Happen?

Flipped Over U: Structural Basis for dsRNA Cleavage by the SARS-CoV-2 Endoribonuclease

Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19 -associated main enzymes

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