Dual‐Locking the SARS‐CoV‐2 Spike Trimer: An Amphipathic Molecular “Bolt” Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition DOI Creative Commons
Shiliang Li, Fang Ye, Yucheng Zheng

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 26, 2025

Abstract The SARS‐CoV‐2 spike (S) protein, a trimeric structure comprising three receptor binding domains (RBDs) and N‐terminal (NTDs), undergoes substantial conformational changes to fusion‐prone open state for angiotensin‐converting enzyme 2 (ACE2) host cell infection. Stabilizing its closed is key antiviral strategy but remains challenging. Here, we introduce S416, novel amphipathic molecule acting as “molecular bolt”. Cryo‐EM study reveals that S416 binds concurrently six sites across two distinct druggable interfaces: molecules at the RBD‐RBD interfaces NTD‐RBD interfaces. This unique “dual‐locking” mechanism, driven by S416's polar carboxyl head nonpolar phenylthiazole tail, robustly stabilizes trimer in locked, conformation through strong inter‐domain interactions, reducing structural flexibility atomic fluctuations compared apo resolved synchronously. Crucially, these are conserved human‐infecting coronaviruses, suggesting potential broad‐spectrum targets. Our findings demonstrate highly dynamic can be effectively stabilized an molecular bolt targeting both inter‐ intra‐monomer interfaces, offering promising against emerging coronaviruses.

Language: Английский

Small Molecule Drugs Targeting Viral Polymerases DOI Creative Commons
Deborah Palazzotti,

Martina Sguilla,

Giuseppe Manfroni

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 661 - 661

Published: May 20, 2024

Small molecules that specifically target viral polymerases—crucial enzymes governing genome transcription and replication—play a pivotal role in combating infections. Presently, approved polymerase inhibitors cover nine human viruses, spanning both DNA RNA viruses. This review provides comprehensive analysis of these licensed drugs, encompassing nucleoside/nucleotide (NIs), non-nucleoside (NNIs), mutagenic agents. For each compound, we describe the specific targeted virus related enzyme, mechanism action, relevant bioactivity data. wealth information serves as valuable resource for researchers actively engaged antiviral drug discovery efforts, offering complete overview established strategies well insights shaping development next-generation therapeutics.

Language: Английский

Citations

8
Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket DOI Creative Commons
Chia‐Ying Huang, A. Metz,

Roland Lange

et al.

Acta Crystallographica Section D Structural Biology, Journal Year: 2024, Volume and Issue: 80(2), P. 123 - 136

Published: Jan. 30, 2024

To identify starting points for therapeutics targeting SARS-CoV-2, the Paul Scherrer Institute and Idorsia decided to collaboratively perform an X-ray crystallographic fragment screen against its main protease. Fragment-based screening was carried out using crystals with a pronounced open conformation of substrate-binding pocket. Of 631 soaked fragments, total 29 hits bound either in active site (24 hits), remote binding pocket (three hits) or at crystal-packing interfaces (two hits). Notably, two fragments pose that sterically incompatible more occluded crystal form were identified. Two isatin-based electrophilic covalently catalytic cysteine residue. The structures also revealed surprisingly strong influence on three published used as positive controls, implications by crystallography.

Language: Английский

Citations

7
Molecules for COVID-19 treatment DOI
Zhigang Zeng,

Changzhou Liao,

Lei Yu

et al.

Chinese Chemical Letters, Journal Year: 2023, Volume and Issue: 35(7), P. 109349 - 109349

Published: Dec. 2, 2023

Language: Английский

Citations

16
A novel nanobody broadly neutralizes SARS‐CoV‐2 via induction of spike trimer dimers conformation DOI Creative Commons
Yang Yang, Junfang Zhang, Shengnan Zhang

et al.

Exploration, Journal Year: 2023, Volume and Issue: 4(3)

Published: Dec. 15, 2023

The ongoing mutations of the SARS-CoV-2 pose serious challenges to efficacy available antiviral drugs, and new drugs with fantastic are always deserved investigation. Here, a nanobody called IBT-CoV144 is reported, which exhibits broad neutralizing activity against by inducing conformation spike trimer dimers. was isolated from an immunized alpaca using RBD wild-type SARS-CoV-2, it showed strong cross-reactive binding potency diverse variants, including Omicron subvariants. Moreover, prophylactically therapeutically intranasal administration confers protective challenge BA.1 variant in BALB/c mice model. structure analysis complex between (S) protein, conducted Cryo-EM, revealed special known as This formed two trimers, six RBDs "up" state bound VHHs. binds lateral region on S facilitating aggregation proteins. results steric hindrance, disrupts recognition virus ACE2 host cells. discovery will provide valuable insights for development advanced therapeutics design next-generation vaccines.

Language: Английский

Citations

15
Efficacy of Nirmatrelvir-Ritonavir versus Azvudine for COVID-19 Treatment in Tibet: A Retrospective Study DOI Creative Commons
Xiang Zhao, Yuan Cheng, Meng Zhang

et al.

Infection and Drug Resistance, Journal Year: 2023, Volume and Issue: Volume 16, P. 6053 - 6060

Published: Sept. 1, 2023

Nirmatrelvir-ritonavir, also known as paxlovid, is a widely used antiviral drug against coronavirus disease 2019 (COVID-19). Azvudine, previously to treat human immunodeficiency virus-1, has been COVID-19 in China. However, only few clinical studies have evaluated the effects of azvudine. Additionally, comparing nirmatrelvir-ritonavir with azvudine limited number.We carried out retrospective case‒control analysis at Third People's Hospital Tibet Autonomous Region. Eighty-two eligible patients who received treatment were included. A total 145 control selected by propensity score matching for age, sex, severity disease, and initial cycle threshold values. comparison nucleic acid test negative conversion time, length hospitalization, mortality rate was conducted.Overall, mean time comparable between groups (7.0 [11.0, 15.0] vs 9.0 [6.0, 12.0] days, P=0.064). mild COVID-19, significantly shorter group than (6.0 [5.0, 8.0] 8.0 11.0] P=0.029). The did not differ hospitalization (8.0 [5.5,10.5] [5.0,10.0] P=0.378). Regarding rate, there 4 (2.8%) deaths 3 (3.7%) (P=0.706).Azvudine generally effective nirmatrelvir-ritonavir, but could suppress virus more rapidly. For those cannot be treated might an therapy COVID-19.

Language: Английский

Citations

14
Potential Anti-SARS-CoV-2 Prodrugs Activated by Phosphorylation and Their Role in the Aged Population DOI Creative Commons
Vivek P. Chavda, Divya Teli, Pankti C. Balar

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(5), P. 2332 - 2332

Published: March 2, 2023

The COVID-19 pandemic has flared across every part of the globe and affected populations from different age groups differently. People aged 40 to 80 years or older are at an increased risk morbidity mortality due COVID-19. Therefore, there is urgent requirement develop therapeutics decrease disease in population. Over last few years, several prodrugs have demonstrated significant anti-SARS-CoV-2 effects vitro assays, animal models, medical practice. Prodrugs used enhance drug delivery by improving pharmacokinetic parameters, decreasing toxicity, attaining site specificity. This article discusses recently explored such as remdesivir, molnupiravir, favipiravir, 2-deoxy-D-glucose (2-DG) their implications population, well investigating recent clinical trials.

Language: Английский

Citations

13
Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication DOI Creative Commons
Li Zhou, Ruochuan Liu,

Heather Pathak

et al.

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(3), P. 879 - 889

Published: Feb. 22, 2024

The highly infectious coronavirus SARS-CoV-2 relies on the viral main protease (Mpro, also known as 3CLpro or Nsp5) to proteolytically process polyproteins encoded by genome for release of functional units in host cells initiate replication. Mpro interacts with proteins innate immune pathways, such IRF3 and STAT1, suppress their activities facilitate virus survival proliferation. To identify mechanism regulating Mpro, we screened various classes E3 ubiquitin ligases found that Parkin RING-between-RING family can induce ubiquitination degradation cell. Furthermore, when undergo mitophagy, PINK1 kinase activates enhances Mpro. We elevated expression significantly decreased replication virus. Interestingly, infection downregulates mouse lung tissues compared healthy controls. These results suggest an antiviral role a ligase targeting potential exploiting virus–host interaction mediated treat infection.

Language: Английский

Citations

5
Identification of amentoflavone as a potent SARS-CoV-2 M pro inhibitor: a combination of computational studies and in vitro biological evaluation DOI
Prabuddha Bhattacharya, Anirban Mandal

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 19

Published: Jan. 23, 2024

Small-molecule inhibitors of SARS-CoV-2 Mpro that block the active site pocket viral main protease have been considered potential therapeutics for development drugs against SARS-CoV-2. Here, we report identification amentoflavone (a biflavonoid) through docking-based virtual screening a library comprised 231 compounds consisting flavonoids and isoflavonoids. The docking results were further substantiated extensive analysis data obtained from all-atom 150 ns MD simulation. End-state effective free energy calculations using MM-PBSA suggested (Ra)-amentoflavone (C3'-C8''-atropisomer) may show greater binding affinity towards than (Sa)-amentoflavone. In vitro cytotoxicity assay established showed high CC50 value indicating much lower toxicity. Further, potent inhibition by was studying effect on HEK293T cells treated with expressing plasmid.

Language: Английский

Citations

4
Magnolol against enterovirus 71 by targeting Nrf2-SLC7A11-GSH pathway DOI Open Access

Dingran Zhao,

Xueyang Guo,

Binbin Lin

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116866 - 116866

Published: June 14, 2024

Enterovirus 71 (EV71), a prominent pathogen associated with hand, foot, and mouth disease (HFMD), has been reported worldwide. To date, the advancement of effective drugs targeting EV71 remains in preliminary experimental stage. In this study, magnolol demonstrated significant dose-dependent inhibition replication vitro. It upregulated overall expression level nuclear factor erythroid 2 - related (Nrf2) facilitated its nucleus translocation, resulting increased various ferroptosis inhibitory genes. This process led to reduction reactive oxygen species (ROS) accumulation induced by viral infection. Additionally, exhibited broad-spectrum antiviral effect against enteroviruses. Notably, treatment substantially enhanced survival rate EV71-infected mice, attenuated load heart, liver, brain, limb tissues, mitigated tissue inflammation. Taken together, emerges as promising candidate for development anti-EV71 drugs.

Language: Английский

Citations

4
Gold nanoparticles combat enveloped RNA virus by affecting organelle dynamics DOI Creative Commons
Fangzhou Li, Qianqian Huang, Ziran Zhou

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 2, 2023

Abstract Enveloped RNA viruses are a group of with an outer membrane derived from host cell and genome consisting ribonucleic acid (RNA). These rely on machinery organelles to replicate assemble new virus particles. However, the interaction between may be disrupted by nanomaterials, such as gold nanoparticles (AuNPs) unique physical chemical properties. In this study, we investigated effects AuNPs different surface charge properties subcellular structure function mammalian cells, their two representative enveloped viruses: lentivirus human coronavirus OC43 (HCoV- OC43) antiviral potential. By comparing properties, found that treatment positive charges induced more significant disruption structures than neutrally charged negatively AuNPs, mainly manifested in lysosomes Cytoskeletal disorders. The effect positively was further evaluated using HCoV-OC43. results showed had inhibitory both HCoV-OC43 without obvious side effects. conclusion, our study provides insights into mechanism action biocompatibility AuNP biological systems, while supporting potential targeting organelle dynamics against viruses.

Language: Английский

Citations

11