Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Silvas, Jesus A.; Jureka, Alexander S.; Nicolini, Anthony M.; Chvatal, Stacie A.; Basler, Christopher F.

doi:10.1101/2020.07.18.210211

Cited by 34 publications

(37 citation statements)

References 56 publications

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“…Our data ( Figure S2B) suggest that PI3K type 3 plays a role in an early step of the viral life cycle, such as endocytosis, fusion, translation or early onset of replication. As recently demonstrated by others, treatment of SARS-CoV-2 infected cells with PI3K type 3 inhibitors causes dispersal of the viral N protein and dsRNA throughout the cytoplasm, suggesting a role of this factor in replication complex formation (Silvas et al, 2020). We showed that disruption of the autophagy genes ATG5 and ATG7, which are required for phagophore expansion, does not negatively impact SARS-CoV-2 and HCoV-229E infection (Figure 2E).…”

Section: Discussionsupporting

confidence: 81%

Identification of TMEM106B as proviral host factor for SARS-CoV-2

Baggen

Persoons

Jansen

et al. 2020

Preprint

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SUMMARYThe ongoing COVID-19 pandemic is responsible for worldwide economic damage and nearly one million deaths. Potent drugs for the treatment of severe SARS-CoV-2 infections are not yet available. To identify host factors that support coronavirus infection, we performed genome-wide functional genetic screens with SARS-CoV-2 and the common cold virus HCoV-229E in non-transgenic human cells. These screens identified PI3K type 3 as a potential drug target against multiple coronaviruses. We discovered that the lysosomal protein TMEM106B is an important host factor for SARS-CoV-2 infection. Furthermore, we show that TMEM106B is required for replication in multiple human cell lines derived from liver and lung and is expressed in relevant cell types in the human airways. Our results identify new coronavirus host factors that may potentially serve as drug targets against SARS-CoV-2 or to quickly combat future zoonotic coronavirus outbreaks.

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Section: Discussionsupporting

confidence: 81%

Identification of TMEM106B as proviral host factor for SARS-CoV-2

Baggen

Persoons

Jansen

et al. 2020

Preprint

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“…4c) suggest that PI3K type 3 facilitates an early step of the viral life cycle, such as endocytosis, fusion, translation or replication initiation. Others reported that PI3K type 3 inhibitors cause dispersal of the SARS-CoV-2 N protein and dsRNA throughout the cytoplasm, suggesting a role of this factor in replication complex formation 35 . We showed that disrupting autophagy genes ATG5 and ATG7, required for phagophore expansion, does not block SARS-CoV-2 and HCoV-229E infection (Fig.…”

Section: Articlesmentioning

confidence: 99%

Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2

et al. 2021

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he COVID-19 pandemic, caused by SARS-CoV-2, has resulted in a worldwide health crisis 1 and few effective drugs are available to treat patients with COVID-19. Although remdesivir initially seemed promising for severe cases 2 , the World Health Organization's Solidarity trial showed that it has no definite impact on mortality 3. Dexamethasone can reduce mortality by a third among critically ill patients with COVID-19, by suppressing the hyperactive immune response 4. However, as treatment benefits severe cases only to a limited extent, efficient and safe therapeutics are urgently required while awaiting the worldwide implementation of vaccines. Coronaviruses cause respiratory and intestinal infections in a broad range of mammals and birds. Seven human coronaviruses (HCoVs) are known, which probably all emerged as zoonoses from bats, mice or domestic animals 5. The four so-called 'common cold HCoVs'-229E, NL63, OC43 and HKU1-cause mild upper respiratory tract illnesses 6. In contrast, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV) and the recently emerged SARS-CoV-2 are highly pathogenic and cause severe, potentially lethal respiratory infections. As numerous coronaviruses reside in animal reservoirs and interspecies transmission frequently occurs 5,7,8 , there is a constant risk of new pathogenic coronaviruses spreading into the human population, as exemplified by the recent SARS-CoV-2 pandemic. Nevertheless, our options to prevent or treat coronavirus infections remain limited. Hence, the development of broad-spectrum anti-coronavirus drugs could help not only to address the current high medical need, but also to quickly contain zoonotic events in the future. Common host factors essential for replication of multiple coronaviruses represent attractive targets for broad-spectrum antiviral drugs. To develop such drugs, it is crucial to understand which host factors coronaviruses require to infect a cell, because each step of the coronavirus replication cycle (receptor binding, endocytosis, fusion, viral protein translation, genome replication, virion assembly and release) may serve as a target for intervention. Although the entry step of coronaviruses has been relatively well characterized, the host-virus interplay in later steps of the viral life cycle remains largely elusive. For SARS-CoV-2, previous studies have shown that the protein angiotensin-converting enzyme 2 (ACE2) can serve as a receptor in Vero E6 cells 9 or in human cells overexpressing ACE2 (refs. 10-12). In addition, it was shown that the SARS-CoV-2 spike (S) can be primed for fusion by cellular proteases such as furin, transmembrane serine protease 2 (TMPRSS2) or cathepsin B or L, depending on the target cell type 10,13. In the present study, we performed a series of genome-wide CRISPR (clustered regularly interspaced short palindromic repeats)-based genetic screens to identify host factors required for SARS-CoV-2 and HCoV-229E infection. We identified phosphoinositide 3-kinase (PI3K) type 3 as a common host factor for SARS-CoV-2,...

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“…Theoretical calculations and practical experimentation alike will be required to develop this technology. [103,104,[196][197][198][199] Spermidine Activator…”

Section: Pharmacological Intervention Targeting Autophagymentioning

confidence: 99%

“…Conclusive studies are still lacking, but potent in vitro inhibition of SARS-CoV-2 replication was recently reported for VPS34-IN1 and VVPS34-IN1 and their analogues, which are inhibitors of vacuolar protein sorting (VPS) 34 (a class III phosphoinositol-3 kinase, PI3K). These inhibitors block autophagy [ 103 , 104 ].…”

Section: The Autophagy-coronavirus Relationshipmentioning

confidence: 99%

“…Among the inhibitors of PI3K commonly employed to block autophagy are 3-methyladenine [ 192 ], wortmannin, LY294002 [ 193 ], PT210 [ 194 ] and GSK-2126458 [ 195 ]. Inhibitors of VPS34 (a PI3K) are VPS34-IN1 and VVPS34-IN1 [ 103 , 104 ], which have antiviral properties against SARS-CoV-2. The analogues of these inhibitors should also be investigated: Spautin-1 [ 196 ], SAR405 [ 197 ], compound 31 [ 198 ] and PIK-III [ 199 ].…”

Section: Pharmacological Intervention Targeting Autophagymentioning

confidence: 99%

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Taming the Autophagy as a Strategy for Treating COVID-19

Garcı́a-Pérez

González-Rojas

Salazar

et al. 2020

Cells

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Currently, an efficient treatment for COVID-19 is still unavailable, and people are continuing to die from complications associated with SARS-CoV-2 infection. Thus, the development of new therapeutic approaches is urgently needed, and one alternative is to target the mechanisms of autophagy. Due to its multifaceted role in physiological processes, many questions remain unanswered about the possible advantages of inhibiting or activating autophagy. Based on a search of the literature in this field, a novel analysis has been made to highlight the relation between the mechanisms of autophagy in antiviral and inflammatory activity in contrast with those of the pathogenesis of COVID-19. The present analysis reveals a remarkable coincidence between the uncontrolled inflammation triggered by SARS-CoV-2 and autophagy defects. Particularly, there is conclusive evidence about the substantial contribution of two concomitant factors to the development of severe COVID-19: a delayed or absent type I and III interferon (IFN-I and IFN-III) response together with robust cytokine and chemokine production. In addition, a negative interplay exists between autophagy and an IFN-I response. According to previous studies, the clinical decision to inhibit or activate autophagy should depend on the underlying context of the pathological timeline of COVID-19. Several treatment options are herein discussed as a guide for future research on this topic.

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Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Cited by 34 publications

References 56 publications

Identification of TMEM106B as proviral host factor for SARS-CoV-2

Identification of TMEM106B as proviral host factor for SARS-CoV-2

Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2

Taming the Autophagy as a Strategy for Treating COVID-19

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