SARS-CoV-2 biology and host interactions.

Since its outbreak in December 2019, the COVID-19 pandemic has caused the death of more than 6.5 million people around the world. The high transmissibility of its causative agent, the SARS-CoV-2 virus, coupled with its potentially lethal outcome, provoked a profound global economic and social crisis. The urgency of finding suitable pharmacological tools to tame the pandemic shed light on the ever-increasing importance of computer simulations in rationalizing and speeding up the design of new drugs, further stressing the need for developing quick and reliable methods to identify novel active molecules and characterize their mechanism of action. In the present work, we aim at providing the reader with a general overview of the COVID-19 pandemic, discussing the hallmarks in its management, from the initial attempts at drug repurposing to the commercialization of Paxlovid, the first orally available COVID-19 drug. Furthermore, we analyze and discuss the role of computer-aided drug discovery (CADD) techniques, especially those that fall in the structure-based drug design (SBDD) category, in facing present and future pandemics, by showcasing several successful examples of drug discovery campaigns where commonly used methods such as docking and molecular dynamics have been employed in the rational design of effective therapeutic entities against COVID-19.

/pdf/lessons-learnt-from-covid-19-computational-strategies-for-1wwh0wfo.pdf

Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830665

Room-temperature structural studies of SARS-CoV-2 protein NendoU with an X-ray free-electron laser

https://doi.org/10.1016/j.coi.2022.102254

Move and countermove: the integrated stress response in picorna- and coronavirus-infected cells

<h2>Summary</h2> Serial femtosecond crystallography (SFX) revolutionized macromolecular crystallography over the past decade by enabling the collection of X-ray diffraction data from nano- or micrometer sized crystals while outrunning structure-altering radiation damage effects at room temperature. The serial manner of data collection from millions of individual crystals coupled with the femtosecond duration of the ultrabright X-ray pulses enables time-resolved studies of macromolecules under near-physiological conditions to unprecedented temporal resolution. In 2020 the rapid spread of the coronavirus SARS-CoV-2 resulted in a global pandemic of coronavirus disease-2019. This led to a shift in how serial femtosecond experiments were performed, along with rapid funding and free electron laser beamtime availability dedicated to SARS-CoV-2-related studies. This review outlines the current state of SFX research, the milestones that were achieved, the impact of the global pandemic on this field as well as an outlook into exciting future directions. 

Review of serial femtosecond crystallography including the COVID-19 pandemic impact and future outlook.

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 a 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.

/pdf/flipped-over-u-structural-basis-for-dsrna-cleavage-by-the-2427jnge.pdf

Flipped over U: structural basis for dsRNA cleavage by the SARS-CoV-2 endoribonuclease.

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.

/pdf/flipped-over-u-structural-basis-for-dsrna-cleavage-by-the-1ocm4r6h.pdf

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9128782

Biochemical Characterization of Emerging SARS-CoV-2 Nsp15 Endoribonuclease Variants

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912914

Exploring cleavage activity of NSP15 using single molecule PIE-FRET

/pdf/biochemical-characterization-of-emerging-sars-cov-2-nsp15-3vfcrem8.pdf

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Flipped over U: structural basis for dsRNA cleavage by the SARS-CoV-2 endoribonuclease.

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

Biochemical Characterization of Emerging SARS-CoV-2 Nsp15 Endoribonuclease Variants

Exploring cleavage activity of NSP15 using single molecule PIE-FRET

Biochemical Characterization of Emerging SARS-CoV-2 Nsp15 Endoribonuclease Variants