Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)

Silva, Roosevelt Alves da

doi:10.1080/07391102.2020.1792992

Cited by 25 publications

(18 citation statements)

References 43 publications

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“…The identification of the C-terminal region of Nsp1 as the key domain for ribosome interactions that are essential for controlling cellular response to viral infections will be helpful in designing attenuated strains of SARS-CoV-2 for vaccine development. Additionally, molecular insights into the Nsp1-mediated translation inhibition could prove valuable for the design and selection of potential Nsp1 small-molecule inhibitors 24 . Our results provide an excellent basis for structure-based experiments aimed at investigating Nsp1 function in vivo by using viral model systems.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation

Schubert

Karousis

Jomaa

et al. 2020

Nat Struct Mol Biol

449

321

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ARS-CoV-2 is the causing agent of the COVID-19 pandemic and belongs to the genus of beta-coronaviruses, with enveloped, positive sense and single-stranded genomic RNA 1. On entering host cells, the viral genomic RNA is translated by the cellular protein synthesis machinery to produce a set of non-structural proteins (NSPs) 2. NSPs render the cellular conditions favorable for viral infection and viral mRNA synthesis 3. Coronaviruses have evolved specialized mechanisms to hijack the host gene expression machinery and employ cellular resources to regulate viral protein production. Such mechanisms are common for many viruses and include inhibition of host protein synthesis and endonucleolytic cleavage of host messenger RNAs (mRNAs) 4,5. In cells infected with the closely related SARS-CoV, one of the most enigmatic viral proteins is the host shutoff factor, Nsp1. Nsp1 is encoded by the gene closest to the 5′ end of the viral genome and is among the first proteins to be expressed after cell entry and infection to repress multiple steps of host protein expression 6-9. Initial structural characterization of the isolated SARS-CoV Nsp1 protein revealed the structure of its N-terminal domain, whereas its C-terminal region was flexibly disordered 10. Furthermore, it was shown that SARS-CoV Nsp1 suppresses host innate immune functions, mainly by targeting type I interferon expression and antiviral signaling pathways 11. Taken together, Nsp1 serves as a potential virulence factor for coronaviruses and represents an attractive target for live attenuated vaccine development 12,13. To provide molecular insights into the mechanism of SARS-CoV-2 Nsp1-mediated translation inhibition, we solved the structures of ribosomal complexes isolated from HEK293 lysates supplemented with recombinant purified Nsp1 as well as of an in vitro reconstituted 40S-Nsp1 complex using cryo-EM. We complement our findings by reporting in vitro and in vivo translation inhibition in the presence of Nsp1 that is relieved after mutating key interacting residues. Furthermore, we show that the translation output of reporters containing full-length viral 5′ untranslated regions (UTRs) is significantly enhanced, which could explain how Nsp1 inhibits global translation while still translating sufficient amounts of viral mRNAs. Results C-terminal domain of SARS-CoV-2 Nsp1 binds to the mRNA entry channel. To elucidate the mechanism of how Nsp1 inhibits translation, we aimed to identify the structures of potential ribosomal complexes as binding targets (Fig. 1). Previously, it has been suggested that Nsp1 mainly targets the ribosome at the translation initiation step 9. We thus treated lysed HEK293E cells with bacterially expressed and purified Nsp1 and loaded the cleared lysate on a sucrose gradient. Fractions containing ribosomal particles were then analyzed for the presence of Nsp1. Interestingly, Nsp1 not only co-migrated with 40S particles, but also with 80S ribosomal complexes (Fig. 1c), suggesting that it interacts with a range of different ribosomal states. W...

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation

Schubert

Karousis

Jomaa

et al. 2020

Nat Struct Mol Biol

449

321

View full text Add to dashboard Cite

show abstract

“…Already published studies in well reputed journals proclaimed that the C-terminal region of SARS-CoV-2 Nsp1 containing 143-180 residues perform an essential role in the inhibition of host protein synthesis [ 5 , 6 , 45 ]. Hence, we adopted a similar binding site (C-terminal region) for docking predicted by the "Find unoccupied pocket" of SeeSAR.…”

Section: Discussionmentioning

confidence: 99%

A computational approach for rational discovery of inhibitors for non-structural protein 1 of SARS-CoV-2

Singh

Bhardwaj

Das

et al. 2021

Computers in Biology and Medicine

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Background Non-structural protein 1 (Nsp1), a virulence agent of SARS-CoV-2, has emerged as an important target for drug discovery. Nsp1 shuts down the host gene function by associating with the 40S ribosomal subunit. Methods Molecular interactions, drug-likeness, physiochemical property predictions, and robust molecular dynamics (MD) simulations were employed to discover novel Nsp1 inhibitors. In this study, we evaluated a series of molecules based on the plant ( Cedrus deodara ) derived α,β,γ -Himachalenes scaffolds. Results The results obtained from estimated affinity and ligand efficiency suggested that BCH10, BCH15, BCH16, and BCH17 could act as potential inhibitors of Nsp1. Moreover, MD simulations comprising various MD driven time-dependent analyses and thermodynamic free energy calculations also suggested stable protein-ligand complexes and strong interactions with the binding site. Furthermore, the selected molecules passed drug likeliness parameters and the physiochemical property analysis showed acceptable bioactivity scores. Conclusion The structural parameters of dynamic simulations revealed that the reported molecules could act as lead compounds against SARS-CoV-2 Nsp1 protein.

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“…This finding is critical for the treatment of SARS-CoV-2, indicating that NSP 1 and the 5' untranslated region might be promising targets for anti- SARS-CoV-2 therapeutics. In a study by Menezes et al [ 168 ], virtual screening was used to discover potential inhibitors of NSP 1 from the DrugBank database. Although these results have not been validated in vitro and in vivo, the three molecules (tirilazad, phthalocyanine, and Zk-806450) obtained from this screen might be potential antiviral drugs.…”

Section: Potential Molecular Targets For Pancoronavirus Antiviral Drumentioning

confidence: 99%

Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection

Liu¹,

Zhang²,

Lü³

et al. 2021

Biomedicine & Pharmacotherapy

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Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)

Cited by 25 publications

References 43 publications

SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation

SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation

A computational approach for rational discovery of inhibitors for non-structural protein 1 of SARS-CoV-2

Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection

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