A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases

Li, Zhizhen; Wu, Jianping; Zhou, Ji; Yuan, Baoshi; Chen, Jiqiao; Wu, Wan-Chen; Mo, Lian; Qu, Zhipeng; Zhou, Fei; Dong, Yingying; Huang, Kai; Liu, Zhiwei; Wang, Tao; Symmes, Deebie; Gu, Jingliang; Sho, Eiketsu; Zhang, Jingping; Chen, Ruihuan; Xu, Ying

doi:10.1128/mbio.02542-21

Cited by 21 publications

(13 citation statements)

References 60 publications

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“…Our experiments suggest that an increased stability of vimentin filaments induces contractile forces, and that these forces also can be increased by the soluble fraction of vimentin. It is important to note that R491-treatment does not eliminate the vimentin ( Li et al, 2021 ; Wu et al, 2021 ). Taken together, these observations suggest that it is the dynamic turnover of vimentin filaments and/or their solubility, and not the presence of vimentin filaments per se that regulates the force exerted over cell-matrix adhesions.…”

Section: Discussionmentioning

confidence: 99%

ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality

Kim

Warrington

López-Guajardo

et al. 2022

Front. Cell Dev. Biol.

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Metastasizing cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumors in the clinic. However, the role of vimentin in cell motility, and if the assembly of non-filamentous variants of vimentin into filaments regulates cell migration remains unclear. We observed that the vimentin-targeting drug ALD-R491 increased the stability of vimentin filaments, by reducing filament assembly and/or disassembly. ALD-R491-treatment also resulted in more bundled and disorganized filaments and an increased pool of non-filamentous vimentin. This was accompanied by a reduction in size of cell-matrix adhesions and increased cellular contractile forces. Moreover, during cell migration, cells showed erratic formation of lamellipodia at the cell periphery, loss of coordinated cell movement, reduced cell migration speed, directionality and an elongated cell shape with long thin extensions at the rear that often detached. Taken together, these results indicate that the stability of vimentin filaments and the soluble pool of vimentin regulate the speed and directionality of cell migration and the capacity of cells to migrate in a mechanically cohesive manner. These observations suggest that the stability of vimentin filaments governs the adhesive, physical and migratory properties of cells, and expands our understanding of vimentin functions in health and disease, including cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality

Kim

Warrington

López-Guajardo

et al. 2022

Front. Cell Dev. Biol.

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“…The importance of endosomal morphology and function for SARS‐CoV‐2 entry was demonstrated in a study reporting alteration of intermediate filaments (IF) to affect both entry and egress steps of SARS‐CoV‐2 (Li et al., 2021c ) (Figure 1 ). Using the pharmacological inhibitor ALD‐491 targeting the class III IF vimentin, the authors reported reduced SARS‐CoV‐2 entry and exosomal release in cell culture‐based assays as well as mitigated disease severity and lung damage in aged mice.…”

Section: Endosomal Trafficking and Sars‐cov‐2 Entrymentioning

confidence: 99%

“…Infection alters the architecture of the ER and the network of DMVs was found to be surrounded by a ‘cage‐like’ vimentin network and pharmacological inhibition of intermediate filaments with Withaferin A reduced SARS‐CoV‐2 replication (Cortese et al., 2020 ). Of note, vimentin appears to have a dual role in the SARS‐CoV‐2 infection cycle, by contributing to viral entry (see section ‘ENDOSOMAL TRAFFICKING AND SARS‐COV‐2 ENTRY’, Figure 1 ) and egress of infectious virus particles (Li et al., 2021c ). It has been shown that newly assembled ß‐coronaviruses exit the cells using lysosomal exocytosis with lysosomes being deacidified and lysosomal enzymes inactivated (Ghosh et al., 2020 ).…”

Section: Secretion and Exosomal Trafficking In Sars‐cov‐2 Infectionmentioning

confidence: 99%

A snapshot of protein trafficking in SARS‐CoV‐2 infection

Bartenschlager

2022

Biology of the Cell

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SARS‐CoV‐2 is a human pathogenic virus responsible for the COVID‐19 (coronavirus disease 2019) pandemic. The infection cycle of SARS‐CoV‐2 involves several related steps, including virus entry, gene expression, RNA replication, assembly of infectious virions and their egress. For all of these steps, the virus relies on and exploits host cell factors, cellular organelles, and processes such as endocytosis, nuclear transport, protein secretion, metabolite transport at membrane contact sites (MSC) and exocytotic pathways. To do this, SARS‐CoV‐2 has evolved multifunctional viral proteins that hijack cellular factors and modulate their function by unique strategies. In this Review, we highlight cellular trafficking factors, processes, and organelles of relevance to the SARS‐CoV‐2 infection cycle and how viral proteins make use of and perturb cellular transport during the viral infection cycle.

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“…A link between extracellular vimentin and SARS-CoV-2 infection has been established by several studies [33,[35][36][37][38]. Vimentin (Vim) is a type III intermediate filament-forming protein and an essential cytoskeleton element.…”

Section: Extracellular Vimentinmentioning

confidence: 99%

Blood-brain barrier function in response to SARS-CoV-2 and its spike protein

Suprewicz

Fiedoruk

Czarnowska

et al. 2023

Neurol Neurochir Pol.

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The typical manifestation of coronavirus 2 (CoV-2) infection is a severe acute respiratory syndrome (SARS) accompanied by pneumonia (COVID-19). However, SARS-CoV-2 can also affect the brain, causing chronic neurological symptoms, variously known as long, post, post-acute, or persistent COVID-19 condition, and affecting up to 40% of patients. The symptoms (fatigue, dizziness, headache, sleep disorders, malaise, disturbances of memory and mood) usually are mild and resolve spontaneously. However, some patients develop acute and fatal complications, including stroke or encephalopathy. Damage to the brain vessels mediated by the coronavirus spike protein (S-protein) and overactive immune responses have been identified as leading causes of this condition. However, the molecular mechanism by which the virus affects the brain still needs to be fully delineated. In this review article, we focus on interactions between host molecules and S-protein as the mechanism allowing the transit of SARS-CoV-2 through the blood-brain barrier to reach the brain structures. In addition, we discuss the impact of S-protein mutations and the involvement of other cellular factors conditioning the pathophysiology of SARS-CoV-2 infection. Finally, we review current and future COVID-19 treatment options.

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A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases

Cited by 21 publications

References 60 publications

ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality

ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality

A snapshot of protein trafficking in SARS‐CoV‐2 infection

Blood-brain barrier function in response to SARS-CoV-2 and its spike protein

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