Two Ligand-Binding Sites on SARS-CoV-2 Non-Structural Protein 1 Revealed by Fragment-Based X-ray Screening DOI Open Access
Shumeng Ma, Shymaa Damfo, Jiaqi Lou

и другие.

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(20), С. 12448 - 12448

Опубликована: Окт. 18, 2022

The regular reappearance of coronavirus (CoV) outbreaks over the past 20 years has caused significant health consequences and financial burdens worldwide. most recent still ongoing novel CoV pandemic, by Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) brought a range devastating consequences. Due to exceptionally fast development vaccines, mortality rate virus been curbed extent. However, limitations vaccination efficiency applicability, coupled with high infection rate, emphasise urgent need for discovering safe effective antivirals against SARS-CoV-2 suppressing its replication or attenuating virulence. Non-structural protein 1 (nsp1), unique viral conserved leader protein, is crucial virulence factor causing host mRNA degradation, interferon (IFN) expression antiviral signalling pathways. In view essential role nsp1 in life cycle, it regarded as an exploitable target drug discovery. Here, we report variety fragment hits N-terminal domain identified fragment-based screening via X-ray crystallography. We also determined structure at atomic resolution (0.99 Å). Binding affinities potential stabilisation were orthogonal biophysical assays such microscale thermophoresis thermal shift assays. two ligand-binding sites on nsp1, one deep shallow pocket, which are not between three medically relevant SARS, MERS coronaviruses. Our study provides excellent starting point more potent nsp1-targeting inhibitors functional studies nsp1.

Язык: Английский

Structural biology of SARS-CoV-2: open the door for novel therapies DOI Creative Commons

Weizhu Yan,

Yanhui Zheng,

Xiao‐Tao Zeng

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Янв. 27, 2022

Abstract Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of pandemic disease COVID-19, which so far without efficacious treatment. The discovery therapy reagents for treating COVID-19 are urgently needed, and structures potential drug-target proteins in viral life cycle particularly important. SARS-CoV-2, a member Orthocoronavirinae subfamily containing largest RNA genome, encodes 29 including nonstructural, structural accessory involved adsorption, entry uncoating, nucleic acid replication transcription, assembly release, etc. These individually act as partner machinery or forming complexes with host cellular factors to participate essential physiological activities. This review summarizes representative typically agents that target SARS-CoV-2 some critical pathogenesis, providing insights into mechanisms underlying infection, prevention Indeed, these studies open door COVID therapies, leading ways prevent treat especially, treatment caused by variants imperative.

Язык: Английский

Процитировано

251
Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion DOI Creative Commons

Setu M. Vora,

Pietro Fontana, Tianyang Mao

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(9)

Опубликована: Фев. 11, 2022

Significance The COVID-19 pandemic and the ever-evolving variants of SARS-CoV-2 are taking a toll on human health. Despite successful rollout vaccines, effective therapies still urgently needed. Our studies here showing that Nsp1 selectively blocks translation host but not viral proteins by proper coordination its N- C-terminal domains to advance our understanding pathogenesis. finding stem-loop 1, highly conserved sequence in 5′ UTR, is necessary sufficient for bypassing Nsp1-mediated shutdown led design antisense oligonucleotides targeting this make susceptible shutdown, interfere with replication, protect SARS-CoV-2–infected mice. This strategy turning SARS-CoV-2’s own virulence against itself could be harnessed therapeutically.

Язык: Английский

Процитировано

93
A computational approach for rational discovery of inhibitors for non-structural protein 1 of SARS-CoV-2 DOI Open Access
Rahul Singh, Vijay Kumar Bhardwaj, Pralay Das

и другие.

Computers in Biology and Medicine, Год журнала: 2021, Номер 135, С. 104555 - 104555

Опубликована: Июнь 8, 2021

Язык: Английский

Процитировано

68
Coronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition DOI Creative Commons
Shuai Yuan,

Shravani Balaji,

Ivan B. Lomakin

и другие.

Frontiers in Microbiology, Год журнала: 2021, Номер 12

Опубликована: Сен. 28, 2021

Coronaviruses have brought severe challenges to public health all over the world in past 20years. SARS-CoV-2, causative agent of COVID-19 pandemic that has led millions deaths, belongs genus beta-coronavirus. Alpha- and beta-coronaviruses encode a unique protein, nonstructural protein 1 (Nsp1) both suppresses host immune responses reduces global gene expression levels cells. As key pathogenicity factor coronaviruses, Nsp1 redirects translation machinery increase synthesis viral proteins. Through multiple mechanisms, coronaviruses impede through Nsp1, while escaping inhibition allow RNA. In this review, we discuss current data about suppression induced by coronavirus as well prospect live-attenuated vaccine development with virulence-attenuated viruses mutations Nsp1.

Язык: Английский

Процитировано

60
Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2 DOI Creative Commons
Mohammad Afsar, Rohan Narayan, Md Noor Akhtar

и другие.

eLife, Год журнала: 2022, Номер 11

Опубликована: Март 24, 2022

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

Язык: Английский

Процитировано

41
Non-Canonical Translation Initiation Mechanisms Employed by Eukaryotic Viral mRNAs DOI Open Access
Ivan I. Sorokin,

Konstantin S. Vassilenko,

Ilya M. Terenin

и другие.

Biochemistry (Moscow), Год журнала: 2021, Номер 86(9), С. 1060 - 1094

Опубликована: Сен. 1, 2021

Язык: Английский

Процитировано

44
A review on structural, non-structural, and accessory proteins of SARS-CoV-2: Highlighting drug target sites DOI Open Access
Md. Jahirul Islam, Nafisa Nawal Islam, Md. Siddik Alom

и другие.

Immunobiology, Год журнала: 2022, Номер 228(1), С. 152302 - 152302

Опубликована: Ноя. 15, 2022

Язык: Английский

Процитировано

35
Cap-independent translation and a precisely located RNA sequence enable SARS-CoV-2 to control host translation and escape anti-viral response DOI Creative Commons
Boris Slobodin, Urmila Sehrawat, Anastasia I. Lev

и другие.

Nucleic Acids Research, Год журнала: 2022, Номер 50(14), С. 8080 - 8092

Опубликована: Июль 18, 2022

Translation of SARS-CoV-2-encoded mRNAs by the host ribosomes is essential for its propagation. Following infection, early expressed viral protein NSP1 binds ribosome, represses translation, and induces mRNA degradation, while elicits an anti-viral response. The mechanisms enabling to escape this multifaceted repression remain obscure. Here we show that expression leads destabilization multi-exon cellular mRNAs, intron-less transcripts, such as interferon genes, relatively stable. We identified a conserved precisely located cap-proximal RNA element devoid guanosines confers resistance NSP1-mediated translation inhibition. Importantly, primary sequence rather than secondary structure critical protection. further genomic 5'UTR SARS-CoV-2 drives cap-independent promotes in eIF4E-independent Torin1-resistant manner. Upon expression, enhances translation. However, sub-genomic 5'UTRs are highly sensitive eIF4E availability, rendering propagation partially Torin1. conclude combined degradation spliced inhibition single-exon along with unique features present 5'UTRs, ensure robust mRNAs. These can be exploited potential therapeutic targets.

Язык: Английский

Процитировано

33
Targeting SARS-CoV-2 Non-Structural Proteins DOI Open Access
W.G. Tam, Ana C. Lorenzo‐Leal, Luis R. Hernández

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(16), С. 13002 - 13002

Опубликована: Авг. 20, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped β that causes disease (COVID-19), leading to a deadly pandemic has claimed millions of lives worldwide. Like other coronaviruses, the SARS-CoV-2 genome also codes for non-structural proteins (NSPs). These NSPs are found within open reading frame 1a (ORF1a) and 1ab (ORF1ab) encode NSP1 NSP11 NSP12 NSP16, respectively. This study aimed collect available literature regarding NSP inhibitors. In addition, we searched natural product database looking similar structures. The results showed structures could be tested as potential inhibitors NSPs.

Язык: Английский

Процитировано

22
Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1 DOI Creative Commons
Ahmed Magdy Khalil, Aitor Nogales, Luis Martínez‐Sobrido

и другие.

Frontiers in Cellular and Infection Microbiology, Год журнала: 2024, Номер 14

Опубликована: Фев. 5, 2024

Following virus recognition of host cell receptors and viral particle/genome internalization, viruses replicate in the via hijacking essential machinery components to evade provoked antiviral innate immunity against invading pathogen. Respiratory infections are usually acute with ability activate pattern (PRRs) in/on cells, resulting production release interferons (IFNs), proinflammatory cytokines, chemokines, IFN-stimulated genes (ISGs) reduce fitness mitigate infection. Nevertheless, game between is a complicated dynamic process, which they restrict each other specific factors maintain their own advantages win this game. The primary role non-structural protein 1 (NS1 Nsp1) influenza A (IAV) pandemic severe respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively, control host-induced immune responses. This review provides comprehensive overview genesis, spatial structure, cellular interactors, mechanisms underlying unique biological functions IAV NS1 SARS-CoV-2 Nsp1 infected cells. We also highlight both proteins modulating replication pathogenicity. Eventually, because important during infection, we describe promising potential as targets for therapy development live attenuated vaccines (LAV). Conclusively, play an virus–host interactions, replication, pathogenesis, pave way develop novel prophylactic and/or therapeutic interventions treatment these human pathogens.

Язык: Английский

Процитировано

7