The heat shock protein 90 inhibitor RGRN-305 attenuates SARS-CoV-2 spike protein-induced inflammation in vitro but lacks effectiveness as COVID-19 treatment in mice DOI Creative Commons
Hakim Ben Abdallah,

Giorgia Marino,

Manja Idorn

et al.

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(9), P. e0310915 - e0310915

Published: Sept. 26, 2024

The inhibition of heat shock protein 90 (HSP90), a molecular chaperone, has been proposed to be potential novel treatment strategy for Coronavirus disease 2019 (COVID-19). In contrast other studies, our data demonstrated that RGRN-305, HSP90 inhibitor, exacerbated the cytopathic effect and did not reduce viral shedding in VeroE6-hTMPRSS2 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Likewise murine model SARS-CoV-2, transgenic mice treated orally RGRN-305 exhibited reduced survival by end experiment (day 12) as 14% (1/7) survived compared 63% (5/8) those drug-vehicle. Animal weight was treatment. Interestingly, we significantly dampened inflammatory response induced SARS-CoV-2 spike human macrophage-like (U937) lung epithelial (A549). Measured quantitative real-time PCR, mRNA expression proinflammatory cytokines TNF , IL1B IL6 were reduced. Together, these suggest exacerbates infection vitro reduces but exhibits strong anti-inflammatory properties. This shows while may helpful ‘cytokine storm’, it no beneficial impact on replication or animals monotherapy. Further animal studies inhibitors combination an anti-viral drug provide additional insights into its utility infections whether continue COVID-19 disease.

Language: Английский

Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration DOI Creative Commons
Elena Gavilán, Rafael Medina-Guzman, Bazhena Bahatyrevich-Kharitonik

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 123 - 123

Published: Jan. 9, 2024

The COVID-19 pandemic has brought to the forefront intricate relationship between SARS-CoV-2 and its impact on neurological complications, including potential links neurodegenerative processes, characterized by a dysfunction of protein quality control systems ER stress. This review article explores role systems, such as Unfolded Protein Response (UPR), Endoplasmic Reticulum-Associated Degradation (ERAD), Ubiquitin–Proteasome System (UPS), autophagy molecular chaperones, in infection. Our hypothesis suggests that produces stress exploits leading disruption proteostasis cannot be solved host cell. culminates cell death may represent link neurodegeneration.

Language: Английский

Citations

12
Fucoidan from Ascophyllum nodosum and Undaria pinnatifida attenuate SARS-CoV-2 infection in vitro and in vivo by suppressing ACE2 and alleviating inflammation DOI

Fang‐Shu Shi,

Yv-Hao Xie,

Yong‐Le Yang

et al.

Carbohydrate Polymers, Journal Year: 2024, Volume and Issue: 332, P. 121884 - 121884

Published: Jan. 29, 2024

Language: Английский

Citations

12
Molecular mechanisms of COVID-19-induced pulmonary fibrosis and epithelial-mesenchymal transition DOI Creative Commons

Peng Pi,

Zhipeng Zeng,

Liqing Zeng

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 3, 2023

As the outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in Hubei Province, China, at end 2019. It has brought great challenges and harms to global public health. SARS-CoV-2 mainly affects lungs is manifested as pulmonary disease. However, one biggest crises arises from emergence COVID-19-induced fibrosis. At present, there are still many questions about how induced fibrosis (PF) occurs treat regulate its long-term effects. In addition, an important process fibrosis, effect on epithelial-mesenchymal transition (EMT) may be factor driving PF. This review summarizes main pathogenesis treatment mechanisms related Starting with basic PF, such EMT, transforming growth factor-β (TGF-β), fibroblasts myofibroblasts, inflammation, macrophages, innate lymphoid cells, matrix metalloproteinases tissue inhibitors metalloproteinases, hedgehog pathway well Notch signaling. Further, we highlight importance EMT PF provide overview molecular mechanisms, which will facilitate future research propose new clinical therapeutic solutions for

Language: Английский

Citations

14
A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication DOI Creative Commons
Yuzheng Zhou,

Zongpeng Chen,

Sijie Liu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: June 27, 2024

Abstract The ORF9b protein, derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting innate response. Despite its significance, precise regulatory mechanisms underlying function remain elusive. In present study, we unveil that of including emerging mutant strains like Delta Omicron, can undergo ubiquitination at K67 site subsequent degradation via proteasome pathway, despite certain mutations among these strains. Moreover, our investigation further uncovers pivotal role translocase outer mitochondrial membrane 70 (TOM70) a substrate receptor, bridging with heat shock 90 alpha (HSP90α) Cullin 5 (CUL5) to form complex. Within this complex, CUL5 triggers ORF9b, acting host antiviral factor, while HSP90α functions stabilize it. Notably, treatment HSP90 inhibitors such GA or 17-AAG accelerates leading pronounced inhibition SARS-CoV-2 replication. Single-cell sequencing data revealed up-regulation lung epithelial cells COVID-19 patients, suggesting potential mechanism which may exploit evade immunity. Our study identifies CUL5-TOM70-HSP90α complex critical regulator stability, shedding light on intricate host–virus response dynamics offering promising avenues drug development against clinical settings.

Language: Английский

Citations

5
Reverse genetics systems for SARS-CoV-2: Development and applications DOI Creative Commons

Hou-Li Cai,

Yao‐Wei Huang

Virologica Sinica, Journal Year: 2023, Volume and Issue: 38(6), P. 837 - 850

Published: Oct. 11, 2023

The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused serious harm to human health and struck a blow global economic development. Research on SARS-CoV-2 has greatly benefited from the use reverse genetics systems, which have been established artificially manipulate viral genome, generating recombinant reporter infectious viruses or biosafety level (BSL-2)-adapted non-infectious replicons with desired modifications. These tools instrumental in studying molecular biological characteristics virus, investigating antiviral therapeutics, facilitating development attenuated vaccine candidates. Here, we review construction strategies, development, applications systems for SARS-CoV-2, may be applied other CoVs as well.

Language: Английский

Citations

13
Hsp90, a team player in protein quality control and the stress response in bacteria DOI
Anushka Wickramaratne, Sue Wickner, Andrea N. Kravats

et al.

Microbiology and Molecular Biology Reviews, Journal Year: 2024, Volume and Issue: 88(2)

Published: March 27, 2024

SUMMARYHeat shock protein 90 (Hsp90) participates in proteostasis by facilitating folding, activation, disaggregation, prevention of aggregation, degradation, and protection against degradation various cellular proteins. It is highly conserved from bacteria to humans. In bacteria, remodeling Hsp90 involves collaboration with the Hsp70 molecular chaperone cochaperones. eukaryotes, folding more complex many cochaperones as well This review focuses primarily on bacterial highlights similarities differences between eukaryotic Hsp90. Seminal research findings that elucidate structure mechanisms reactivation promoted are discussed. Understanding will provide fundamental insight into systems.

Language: Английский

Citations

4
HSP90AB1 is a host factor that promotes porcine deltacoronavirus replication DOI Creative Commons
Yujia Zhao,

Jianlin Yuan,

Dai Xiao

et al.

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 300(1), P. 105536 - 105536

Published: Dec. 12, 2023

Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus. It causes mortality in neonatal piglets and of growing concern because its broad host range, including humans. To date, the mechanism PDCoV infection remains poorly understood. Here, based on a genome-wide CRISPR screen PDCoV-infected cells, we found that HSP90AB1 (heat shock protein 90 alpha family class B1) promotes infection. Knockdown or KO LLC-PK cells resulted significantly suppressed Infected treated with HSP90 inhibitors 17-AAG VER-82576 also showed infection, although KW-2478, which does not affect ATPase activity HSP90AB1, had no effect We interacts N, NS7, NSP10 proteins PDCoV. further evaluated interaction between N C-tail domain HSP90AB1-interacting domain. Further studies protects from degradation via proteasome pathway. In summary, our results reveal key role for contribute to provide new targets antiviral research.

Language: Английский

Citations

10
Novel Hsp90α inhibitor inhibits HSV-1 infection by suppressing the Akt/β-catenin pathway DOI
Zexu Wang,

Weixiangmin Zou,

Qiongzhen Zeng

et al.

International Journal of Antimicrobial Agents, Journal Year: 2025, Volume and Issue: 65(3), P. 107448 - 107448

Published: Jan. 23, 2025

Language: Английский

Citations

0
Advancing Viral Defense: Unravelling the Potential of Host-Directed Antivirals Against SARS-CoV-2 DOI Creative Commons
Zheng Yao Low, Siau Wui Chin, Sharifah Syed Hassan

et al.

Drugs and Drug Candidates, Journal Year: 2025, Volume and Issue: 4(2), P. 13 - 13

Published: March 28, 2025

The COVID-19 pandemic, driven by the high transmissibility and immune evasion caused SARS-CoV-2 its variants (e.g., Alpha, Delta, Omicron), has led to massive casualties worldwide. As of November 2024, International Committee on Taxonomy Viruses (ICTV) identified 14,690 viral species across 3522 genera. increasing infectious resistance FDA EMA-approved antivirals, such as 300-fold efficacy reduction in Nirmatrelvir against 3CLpro, highlight need for mutation-stable likewise targeting essential host proteins like kinases, heat shock proteins, lipid metabolism immunological pathway etc. Unlike direct-acting HDAs reduce risk conserved replication. proposal repurposing current FDA-approved drugs host-directed antiviral (HDA) approach is not new, Ouabain, a sodium-potassium ATPase inhibitor herpes simplex virus (HSV) Verapamil, calcium channel blocker influenza A (IAV), name few. Given colossal potential HDA exterminate infection, it been increasingly studied SARS-CoV-2. This review aims unravel interaction between viruses human hosts their successfully proposed provide insight into an alternative treatment rampant mutation benefits, limitations, protein-targeted therapies prospects are also covered this review.

Language: Английский

Citations

0
F-box only protein 10 protects against kidney tubulointerstitial fibrosis by inhibiting ACSL4-mediated lipid peroxidation and ferroptosis DOI
Jinping Hu,

Feng Ma,

Xinping Chen

et al.

Cellular Signalling, Journal Year: 2025, Volume and Issue: unknown, P. 111841 - 111841

Published: April 1, 2025

Language: Английский

Citations

0