SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development

Murgolo, Nicholas; Therien, Alex G.; Howell, Bonnie J.; Klein, Daniel; Koeplinger, Kenneth A.; Lieberman, Linda A.; Adam, Gregory C.; Flynn, Jessica A.; McKenna, Philip M.; Swaminathan, Gokul; Hazuda, Daria J.; Olsen, David B.

doi:10.1371/journal.ppat.1009225

Cited by 186 publications

(197 citation statements)

References 112 publications

Supporting

Mentioning

169

Contrasting

Order By: Relevance

“…Mechanistically, the different infectivity of cells expressing high levels of TMPRSS2 is probably explained by the fact that WT SARS-CoV-2 S is cleaved at the furin cleavage site (S1/S2 cleavage), which primes S for cleavage with TMPRSS2 (at S2’) resulting in activation of the fusion peptide 1 . The virus can then fuse at the plasma membrane to enter cells 20, 22 . It has been shown that the furin-cleaved S can also interact with neuropilin (NRP1) following the CendR rule, potentially enhancing viral entry 34, 35 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis for cell-type specific evolution of viral fitness by SARS-CoV-2

Gupta

Toelzer

Williamson

et al. 2021

Preprint

View full text Add to dashboard Cite

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants which is of particular concern due to their potential for increased transmissibility and pathology. In addition to this entrenched variant diversity in circulation, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriSΔ variant, originally identified as a viral subpopulation by passaging SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike glycoprotein an eight amino-acid deletion encompassing the furin recognition motif and S1/S2 cleavage site. Here, we analyzed the structure, function and molecular dynamics of this variant spike, providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity, allowing the virus to probe diverse trajectories in distinct cell types to evolve viral fitness.

show abstract

Section: Discussionmentioning

confidence: 99%

Structural basis for cell-type specific evolution of viral fitness by SARS-CoV-2

Gupta

Toelzer

Williamson

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…1A) and apilimod (Fig. 1B) (19,25,26). While this mutation has no effect on the virus entry mechanism or sensitivity to proteases, it stabilizes the stalk region of the spike, which otherwise tend to fall apart after furin cleavage between S1 and S2 (27)(28)(29)(30).…”

Section: Combined Use Of Apilimod and Camostat Mesylate Led To Enhanced Inhibition Of Vsv-mentioning

confidence: 99%

Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease

Kreutzberger

Sanyal

Ojha

et al. 2021

Preprint

View full text Add to dashboard Cite

Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike S protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic, and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ~5-10 fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both, a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2 virus. The substantial ~5 fold or more decrease of half maximal effective concentrations (EC50 values) suggests a plausible treatment strategy based on the combined use of these inhibitors.

show abstract

“…Then the genomic RNA undergoes replication and translation to form new virions after assembly in ERGIC, and the new viruses then are released into the outside of the cell. 43 , 44 Previous studies showed that NRPs are known to mediate the internalization of CendR ligands through an endocytosis resembling micropinocytosis but it is unclear whether NRP1 allows attachment and receptor-mediated endocytosis in SARS-CoV-2 infected patients. 6 , 22 , 45 , 46 Thus, further studies need to be done to clearly explain the role of NRP1 in the entry and infection mechanisms of SARS-CoV-2.…”

Section: Neuropilin 1 and Covid-19mentioning

confidence: 99%

Neuropilin 1: A Novel Entry Factor for SARS-CoV-2 Infection and a Potential Therapeutic Target

Abebe¹,

Ayele²,

Muche³

et al. 2021

BTT

View full text Add to dashboard Cite

SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development

Cited by 186 publications

References 112 publications

Structural basis for cell-type specific evolution of viral fitness by SARS-CoV-2

Structural basis for cell-type specific evolution of viral fitness by SARS-CoV-2

Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease

Neuropilin 1: A Novel Entry Factor for SARS-CoV-2 Infection and a Potential Therapeutic Target

Contact Info

Product

Resources

About