Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2

Kang, Yuan Lin; Chou, Yi Ying; Rothlauf, Paul W.; Liu, Zhuoming; Soh, Timothy K.; Cureton, David K.; Case, James Brett; Chen, Rita E.; Diamond, Michael S.; Whelan, Sean P. J.; Kirchhausen, Tom

doi:10.1073/pnas.2007837117

Cited by 162 publications

(149 citation statements)

References 52 publications

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“…4b) 54 . Similar antiviral activity was previously demonstrated with apilimod, another PIKfyve inhibitor [55][56][57] .…”

Section: Compounds Directed At Host Factors Inhibit Coronavirus Replisupporting

confidence: 83%

“…Additionally, phosphatidylinositol biosynthesis was uncovered as an important pathway for coronavirus infection. While PIKfyve has previously been implicated through chemical inhibition [55][56][57] , we identified the upstream PI3K complex as a new critical host factor, potentially exhibiting pan-coronavirus function. Due to its involvement in multiple cellular processes including vesicular trafficking and autophagy 28 , it remains to be determined whether coronaviruses hijack this pathway during entry or for the generation of doublemembrane vesicles required for the viral replication/transcription complexes.…”

Section: Discussionmentioning

confidence: 92%

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Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Wang

Simoneau

Kulsuptrakul

et al. 2020

Preprint

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The Coronaviridae are a family of viruses that causes disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors that are common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted parallel genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E) and glycosaminoglycans (for OC43). Additionally, we discovered phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle as well as the potential development of host-directed therapies.

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“…4b) 54 . Similar antiviral activity was previously demonstrated with apilimod, another PIKfyve inhibitor [55][56][57] .…”

Section: Compounds Directed At Host Factors Inhibit Coronavirus Replisupporting

confidence: 83%

Section: Discussionmentioning

confidence: 92%

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Wang

Simoneau

Kulsuptrakul

et al. 2020

Preprint

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“…Indeed, PIKFYVE , another endosomal viral processing factor, was also broadly expressed in hESC-CMs (Supplementary Fig. 1c) 26 . Despite the low levels of mRNA, ACE2 protein was strongly expressed in hPSC-CMs derived from multiple lines (RUES2 female hESCs, H7 female hESCs, and WTC11c male hiPSCs), reaching levels comparable to those of VERO cells, a primate kidney epithelial line with established SARS-CoV-2 tropism (Fig.…”

Section: Main Textmentioning

confidence: 97%

“…A larger fraction of cells expressed moderate to high levels of endosomal cysteine proteases CTSB (cathepsin B; ~71.0%) and CTSL (cathepsin L; ~46.0%). Detection of these factors is relevant because they can cleave the spike glycoprotein and lead to endomembrane fusion-mediated release of SARS-CoV-2 genome inside the cytoplasm 15,25,26 . Importantly, these viral processing factors were often co-expressed with ACE2 (Supplementary Fig.…”

Section: Main Textmentioning

confidence: 99%

SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function

Marchianò

Hsiang

Higashi

et al. 2020

Preprint

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Global health has been threatened by the COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2)1. Although considered primarily a respiratory infection, many COVID-19 patients also suffer severe cardiovascular disease2–4. Improving patient care critically relies on understanding if cardiovascular pathology is caused directly by viral infection of cardiac cells or indirectly via systemic inflammation and/or coagulation abnormalities3,5–9. Here we examine the cardiac tropism of SARS-CoV-2 using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and three-dimensional engineered heart tissues (3D-EHTs). We observe that hPSC-CMs express the viral receptor ACE2 and other viral processing factors, and that SARS-CoV-2 readily infects and replicates within hPSC-CMs, resulting in rapid cell death. Moreover, infected hPSC-CMs show a progressive impairment in both electrophysiological and contractile properties. Thus, COVID-19-related cardiac symptoms likely result from a direct cardiotoxic effect of SARS-CoV-2. Long-term cardiac complications might be possible sequelae in patients who recover from this illness.

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“…The Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve, UniProt ID: Q9Y2I7) is a protein and lipid kinase involved in endocytosis [ 195 ]. SARS-CoV-2 entry is significantly reduced by PIKfyve inhibitors, vacuolin-1 or apilimod, a small molecule investigated in Crohn’s disease and psoriasis [ 196 ]. To date, no experimental structure of PIKfyve has been made available.…”

Section: Overview Of Some Of the Applications Of Structural Bioinformmentioning

confidence: 99%

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Waman¹,

Sen²,

Váradi³

et al. 2020

Briefings in Bioinformatics

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SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design. Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics. Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor–antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

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Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2

Cited by 162 publications

References 52 publications

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

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