Emerging Mutations in Nsp1 of SARS-CoV-2 and Their Effect on the Structural Stability

Mou, Ke‐Jie; Mukhtar, Farwa; Khan, Muhammad Tahir; Darwish, Doaa Bahaa Eldin; Peng, Shaoliang; Muhammad, Shabbir; Al‐Sehemi, Abdullah G.; Wei, Dong‐Qing

doi:10.3390/pathogens10101285

Cited by 27 publications

(20 citation statements)

References 50 publications

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“…This protein has been proposed as a target for vaccine development and also for drug design. The majority of mutations occuring in NSP1 exhibited a destabilizing effect and increased flexibility [119].…”

Section: Mutations In Nsp5mentioning

confidence: 99%

Follow-up investigation and detailed mutational characterization of the SARS-CoV-2 Omicron variant lineages (BA.1, BA.2, BA.3 and BA.1.1)

Abbas

Kusakin

Sharrouf

et al. 2022

Preprint

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Aided by extensive protein mutations, the SARS-CoV-2 Omicron (B.1.1.529) variant overtook the previously dominant Delta variant and rapidly spread around the world. It was shown to exhibit significant resistance to current vaccines and evasion from neutralizing antibodies. It is therefore critical to investigate the Omicron mutations trajectories. In this study, a literature search of published articles and SARS-CoV-2 databases was conducted, We explored the full list of mutations in Omicron BA.1, BA.1.1, BA.2, and BA.3 lineages. We described in detail the prevalence and occurrence of the mutations across variants, and how Omicron differs from them. We used GISAID as our primary data source, which provides open access to genomics data of the SARS-CoV-2 virus, in addition to epidemiological and geographical data. We examined how these mutations interact with each other, their co-occurrence and clustering. Our study offers for the first time a comprehensive description of all mutations with a focus on non-spike mutations and demonstrated that mutations in regions other than the Spike (S) genes are worth investigating further. Our research established that the Omicron variant has retained some mutations reported in other SARS-CoV-2 variants, yet many of its mutations are extremely rare in other variants and unique to Omicron. Some of these mutations have been linked to the transmissibility and immune escape of the virus, and indicate a significant shift in SARS-CoV-2 evolution. The most likely theories for the evolution of the Omicron variant were also discussed.

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Section: Mutations In Nsp5mentioning

confidence: 99%

Follow-up investigation and detailed mutational characterization of the SARS-CoV-2 Omicron variant lineages (BA.1, BA.2, BA.3 and BA.1.1)

Abbas

Kusakin

Sharrouf

et al. 2022

Preprint

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“…Moreover, Nsp1 interacts with host mRNA export receptor NXF1-NXT1 heterodimer and aids in retention of cellular mRNAs in the nucleus ( Zhang et al, 2021 ). Further, Mou et al, 2021 deciphered the frequency of mutation accumulation in the N-terminal domain was higher than that of the C-terminal domain ( Mou et al, 2021 ). Therefore, we targeted the C-terminal helices of Nsp for this study.…”

Section: Discussionmentioning

confidence: 99%

Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2

Afsar

Narayan²,

Akhtar

et al. 2022

eLife

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The SARS-CoV-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. The C-terminal helices of Nsp1 (Nsp1-C-ter) from SARS-CoV-2 bind in the mRNA entry channel of the 40S ribosomal subunit and blocks mRNA entry, thereby shutting down host protein synthesis. Nsp1 suppresses host immune function and is vital for viral replication. Hence, Nsp1 appears to be an attractive target for therapeutics. In this study, we have in silico screened Food and Drug Administration (FDA)-approved drugs against Nsp1-C-ter. Among the top hits obtained, montelukast sodium hydrate binds to Nsp1 with a binding affinity (KD) of 10.8±0.2 µM in vitro. It forms a stable complex with Nsp1-C-ter in simulation runs with -95.8±13.3 kJ/mol binding energy. Montelukast sodium hydrate also rescues the inhibitory effect of Nsp1 in host protein synthesis, as demonstrated by the expression of firefly luciferase reporter gene in cells. Importantly, it shows antiviral activity against SARS-CoV-2 with reduced viral replication in HEK cells expressing ACE2 and Vero-E6 cells. We, therefore, propose montelukast sodium hydrate can be used as a lead molecule to design potent inhibitors to help combat SARS-CoV-2 infection.

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“…Similarly, in some less frequent mutants like D48G NSP1, an increase in molecular flexibility was detected at AA residues S40, R43, Q44, K47, and G48. These alerts in AAS might have effects on its natural function in terms of blocking host mRNA translation and evading the immune system (35).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Non-Structural Protein 1(NSP1) Mutation Virulence and Natural Selection: Evolutionary Trends in the Six Continents

Ghaleh

Rahimian

Mahmanzar

et al. 2022

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unsegmented positive-sense single-stranded RNA virus that belongs to the β-coronavirus. This virus was the cause of a novel severe acute respiratory syndrome in 2019 (COVID-19) that emerged in Wuhan, China at the early stage of the pandemic and rapidly spread around the world. Rapid transmission and reproduction of SARS-CoV-2 threaten worldwide health with a high mortality rate from the virus. According to the significant role of non-structural protein 1 (NSP1) in inhibiting host mRNA translation, this study focuses on the link between amino acid sequences of NSP1 and alterations of them spreading around the world. The SARS-CoV-2 NSP1 protein sequences were analyzed and FASTA files were processed by Python language programming libraries. Reference sequences compared with each NSP1 sample to identify every mutation and categorize them were based on continents and frequencies. NSP1 mutations rate divided into continents were different. Based on continental studies, E87D in global vision and also in Europe notably increased. The E87D mutation has significantly risen especially in the last months of the study as the first frequent mutation observed. The remarkable mutations, H110Y and R24C, have the second and third frequencies, respectively. Based on this mutational information, despite NSP1 being a conserved sequence occurrence, these mutations change the rate of flexibility and stability of the NSP1 protein, which can eventually affect inhibiting the host translation.

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Emerging Mutations in Nsp1 of SARS-CoV-2 and Their Effect on the Structural Stability

Cited by 27 publications

References 50 publications

Follow-up investigation and detailed mutational characterization of the SARS-CoV-2 Omicron variant lineages (BA.1, BA.2, BA.3 and BA.1.1)

Follow-up investigation and detailed mutational characterization of the SARS-CoV-2 Omicron variant lineages (BA.1, BA.2, BA.3 and BA.1.1)

Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2

SARS-CoV-2 Non-Structural Protein 1(NSP1) Mutation Virulence and Natural Selection: Evolutionary Trends in the Six Continents

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