A Biochemical Perspective of the Nonstructural Proteins (NSPs) and the Spike Protein of SARS CoV-2

Yoshimoto, F. K.

doi:10.1007/s10930-021-09967-8

Cited by 26 publications

(29 citation statements)

References 110 publications

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“…Like other coronaviruses, SARS-CoV-2 is a positive-strand single-stranded RNA virus (+ssRNA), with a linear segment of RNA of approximately 30,000 bases, larger than any other RNA virus. SARS-CoV-2 virions, which are 60–140 nm in diameter, have four structural proteins: the spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins and 16 non-structural proteins (Nsp1–16) [ 6 , 7 , 8 , 9 ]. The nucleocapsid protein wraps around the RNA genome, encapsulated within an envelope associated with the S, E and M proteins [ 10 ].…”

Section: Sars-cov-2 Structuresmentioning

confidence: 99%

“…The RNA-dependent RNA polymerase Nsp12 is important in the replication and transcription of the viral genome and forms a core polymerase complex with Nsp7 and Nsp8 [ 19 ]. The helicase Nsp13 binds ATP and participates in viral genome replication and transcription [ 7 ]. Nsp14 has dual activities: guanosine N7-methyltransferase activity and exoribonuclease activity; it is critical for the replication of SARS-CoV-2 [ 20 ].…”

Section: Sars-cov-2 Structuresmentioning

confidence: 99%

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Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion

Salleh

Derrick

Deris

2021

IJMS

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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents significant social, economic and political challenges worldwide. SARS-CoV-2 has caused over 3.5 million deaths since late 2019. Mutations in the spike (S) glycoprotein are of particular concern because it harbours the domain which recognises the angiotensin-converting enzyme 2 (ACE2) receptor and is the target for neutralising antibodies. Mutations in the S protein may induce alterations in the surface spike structures, changing the conformational B-cell epitopes and leading to a potential reduction in vaccine efficacy. Here, we summarise how the more important variants of SARS-CoV-2, which include cluster 5, lineages B.1.1.7 (Alpha variant), B.1.351 (Beta), P.1 (B.1.1.28/Gamma), B.1.427/B.1.429 (Epsilon), B.1.526 (Iota) and B.1.617.2 (Delta) confer mutations in their respective spike proteins which enhance viral fitness by improving binding affinity to the ACE2 receptor and lead to an increase in infectivity and transmission. We further discuss how these spike protein mutations provide resistance against immune responses, either acquired naturally or induced by vaccination. This information will be valuable in guiding the development of vaccines and other therapeutics for protection against the ongoing coronavirus disease 2019 (COVID-19) pandemic.

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Section: Sars-cov-2 Structuresmentioning

confidence: 99%

Section: Sars-cov-2 Structuresmentioning

confidence: 99%

Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion

Salleh

Derrick

Deris

2021

IJMS

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“…The viral non-structural NSP13 protein interacts with six proteins encoded by genes (GOLGA2, GOLGA3, GOLGB1, TBK1, FYCO1, and PDE4DIP) sharing mutations in familial sarcoidosis (Table S1). NSP13 belongs to the NSP1-16 replicase-transcriptase complex (RTC) of SARS-CoV2 and encodes a helicase/triphosphatase [71]. Golgins regulate the Golgi architecture, cell polarity and migration, membrane trafficking, endocytic vesicles and fusion with lysosomes, and, finally, autophagy in close interaction with various Rho GTPases such as Rab, Rac1/Cdc42, and RhoA [72].…”

Section: Rho Gtpases Related Pathwaysmentioning

confidence: 99%

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

Pachéco

Valeyre

Jammal

et al. 2021

Cells

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Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.

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“…non-structural protein 5 (nsp5), self-cleaves the parent polypeptide at its n-terminal (nsp4/5) and c-terminal (nsp5/6) and is liberated to form a homodimer. This homodimer further cleaves the polyprotein using its catalytic dyad that contains the catalytic residues Histidine 41 (His-41) and Cysteine 145 (Cys-145) 25 . The 3CLpro of SARS-CoV-2 is 96.1% identical to that of SARS-CoV-1, with a 99% similarity suggesting the highest conservancy than any other target within the SARS-CoV-2 genome.…”

Section: Introductionmentioning

confidence: 99%

Antiviral evaluation of hydroxyethylamine analogs: Inhibitors of SARS-CoV-2 main protease (3CLpro), a virtual screening and simulation approach

Gupta

Kumar

Zak

et al. 2021

Bioorganic & Medicinal Chemistry

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The continued toll of COVID-19 has halted the smooth functioning of civilization on a global scale. With a limited understanding of all the essential components of viral machinery and the lack of structural information of this new virus, initial drug discovery efforts had limited success. The availability of high-resolution crystal structures of functionally essential SARS-CoV-2 proteins, including 3CLpro, supports the development of target-specific therapeutics. 3CLpro, the main protease responsible for the processing of viral polypeptide, plays a vital role in SARS-CoV-2 viral replication and translation and is an important target in other coronaviruses. Additionally, 3CLpro is the target of repurposed drugs, such as lopinavir and ritonavir. In this study, target proteins were retrieved from the protein data bank (PDB IDs: 6M03, 6LU7, 2GZ7, 6W63, 6SQS, 6YB7, and 6YVF) representing different open states of the main protease to accommodate macromolecular substrate. A hydroxyethylamine (HEA) library was constructed from harvested chemical structures from all the series being used in our laboratories for screening against malaria and Leishmania parasites. The database consisted of ∼1000 structure entries, of which 70% were new to ChemSpider at the time of screening. This in-house library was subjected to high throughput virtual screening (HTVS), followed by standard precision (SP) and then extra precision (XP) docking (Schrodinger LLC 2021). The ligand strain and complex energy of top hits were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Promising hit compounds (n=40) specifically binding to 3CLpro with high energy and average MM/GBSA scores were then subjected to (100-ns) MD simulations. Using this sequential selection followed by an in-silico validation approach, we found a promising HEA-based compound (N,N'-((3S,3'S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))bis(2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanamide)), which showed high in vitro antiviral activity against SARS-CoV-2. Further to reduce the size of the otherwise larger ligand, a pharmacophore-based predicted library of ∼42 derivatives was constructed, which were added to the previous compound library and rescreened virtually. Out of several hits from the predicted library, two compounds were synthesized, tested against SARS-CoV-2 culture, and found to have markedly improved antiviral activity.

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A Biochemical Perspective of the Nonstructural Proteins (NSPs) and the Spike Protein of SARS CoV-2

Cited by 26 publications

References 110 publications

Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion

Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

Antiviral evaluation of hydroxyethylamine analogs: Inhibitors of SARS-CoV-2 main protease (3CLpro), a virtual screening and simulation approach

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