Lessons Learned and Yet-to-Be Learned on the Importance of RNA Structure in SARS-CoV-2 Replication

Bassett, Maclean; Salemi, Marco; Magalis, Brittany Rife

doi:10.1128/mmbr.00057-21

Cited by 9 publications

(9 citation statements)

References 276 publications

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“…Maps and reference structures for four alternative conformations of the SL5 domain from 5′UTR from the Bat coronavirus BtCoV‐HKU5 were provided for assessment in this CASP. This domain is known to have a conserved secondary structure in many coronaviruses, 32,33 which is thought to be important in the packaging of viral particles during infection 34 . Maps for this target varied in resolution from 5.6 to 7.6 Å.…”

Section: Resultsmentioning

confidence: 99%

“…This domain is known to have a conserved secondary structure in many coronaviruses, 32,33 which is thought to be important in the packaging of viral particles during infection. 34 Maps for this target varied in resolution from 5.6 to 7.6 Å. The four refined predictions for the third conformation (R1156v3) exhibited average SMOC values slightly higher than the reference structure.…”

Section: Overall Rna Model Analysismentioning

confidence: 99%

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CASP15 cryo‐EM protein and RNA targets: Refinement and analysis using experimental maps

Mulvaney,

Kretsch,

Elliott

et al. 2023

Proteins

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CASP assessments primarily rely on comparing predicted coordinates with experimental reference structures. However, experimental structures by their nature are only models themselves—their construction involves a certain degree of subjectivity in interpreting density maps and translating them to atomic coordinates. Here, we directly utilized density maps to evaluate the predictions by employing a method for ranking the quality of protein chain predictions based on their fit into the experimental density. The fit‐based ranking was found to correlate well with the CASP assessment scores. Overall, the evaluation against the density map indicated that the models are of high accuracy, and occasionally even better than the reference structure in some regions of the model. Local assessment of predicted side chains in a 1.52 Å resolution map showed that side‐chains are sometimes poorly positioned. Additionally, the top 118 predictions associated with 9 protein target reference structures were selected for automated refinement, in addition to the top 40 predictions for 11 RNA targets. For both proteins and RNA, the refinement of CASP15 predictions resulted in structures that are close to the reference target structure. This refinement was successful despite large conformational changes often being required, showing that predictions from CASP‐assessed methods could serve as a good starting point for building atomic models in cryo‐EM maps for both proteins and RNA. Loop modeling continued to pose a challenge for predictors, and together with the lack of consensus amongst models in these regions suggests that modeling, in combination with model‐fit to the density, holds the potential for identifying more flexible regions within the structure.

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Section: Resultsmentioning

confidence: 99%

Section: Overall Rna Model Analysismentioning

confidence: 99%

CASP15 cryo‐EM protein and RNA targets: Refinement and analysis using experimental maps

Mulvaney,

Kretsch,

Elliott

et al. 2023

Proteins

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“…When the human immune system produces antibodies, it recognizes this spike protein and produces antibodies that match its shape. Inside the sphere is an RNA genome of approximately 30 kb, the largest known RNA viral genome, bound to a protein called nucleocapsid, which consists of the N protein, the most abundant protein in viral particles [ 27 , 28 ]. The outer nucleocapsid is enveloped and consists of lipid membranes, which are easily destroyed by washing with soap and detergent or disinfecting with alcohol, rendering the virus infective.…”

Section: Structural Characterization Of Sars-cov-2mentioning

confidence: 99%

Extracellular Vesicle-Based SARS-CoV-2 Vaccine

Matsuzaka

Yashiro

2023

Vaccines

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Messenger ribonucleic acid (RNA) vaccines are mainly used as SARS-CoV-2 vaccines. Despite several issues concerning storage, stability, effective period, and side effects, viral vector vaccines are widely used for the prevention and treatment of various diseases. Recently, viral vector-encapsulated extracellular vesicles (EVs) have been suggested as useful tools, owing to their safety and ability to escape from neutral antibodies. Herein, we summarize the possible cellular mechanisms underlying EV-based SARS-CoV-2 vaccines.

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“…Most of the recently‐evolved highly pathogenic viruses, for example, the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), are RNA in nature (i.e., RNA viruses) (Griffin, 2022; International Committee on Taxonomy of Viruses Executive Committee, 2020). Interestingly, the high attractiveness of the viral RNA in medicinal and therapeutic chemistry comes mainly from, first, its unique ability to encode diverse information and functions (including regulating the virus's own genome replication as well as interacting with host ribosomes) in its sequential structure; second, the slight differences in the biochemical synthetic pathways between the viral and human RNAs (this provides significant beneficial drug selectivity and specificity); third, the high number of highly‐conserved viral enzymes that act on viral RNAs (this provides richness and broadness in drug action); and, fourth, the usual relative long‐term persistence of viral RNAs after acute infection recoveries in humans and other hosts (this provides feasible pathways and choices for tracking and curing the long‐term sequelae of such viral infections/diseases) (Bassett et al., 2022; Griffin, 2022; Rabie, 2022a, 2022b; Rabie et al., 2023).…”

Section: Figurementioning

confidence: 99%

RNA: The most attractive target in recent viral diseases

Rabie

2023

Chem Biol Drug Des

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As an expert in the field of drug design and discovery, I tried, in this up‐to‐date perspective or commentary article, to recap and shed light on the previous and latest revolutionary strategies employed in medicinal and therapeutic chemistry to target the principal viral weapon used by virulent RNA viruses (e.g., the severe acute respiratory syndrome coronavirus 2 “SARS‐CoV‐2”) to infect humans and spread infections, the genomic RNA strands. These strategies act by taking advantage of the weakness points of this attractive bioweapon to disable or attack it (itself), accordingly stop the entire viral reproduction, and effectively end the severe microbial infections such as the coronavirus disease 2019 (COVID‐19). The generation of respective slightly falsely‐weaved RNA strands, either endogenously or exogenously, is the principal key for designing most of these therapeutic approaches.

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Lessons Learned and Yet-to-Be Learned on the Importance of RNA Structure in SARS-CoV-2 Replication

Cited by 9 publications

References 276 publications

CASP15 cryo‐EM protein and RNA targets: Refinement and analysis using experimental maps

CASP15 cryo‐EM protein and RNA targets: Refinement and analysis using experimental maps

Extracellular Vesicle-Based SARS-CoV-2 Vaccine

RNA: The most attractive target in recent viral diseases

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