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10.1371/journal.pcbi.1008461 http://scihub22266oqcxt.onion/10.1371/journal.pcbi.1008461 33290397!7748278!33290397     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=33290397&cmd=llinks): Failed to open stream: HTTP request failed! 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Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection |pdf=|usr=}}{{33290397}} gab.com Text Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection JO: PLoS Comput Biol http://www.kidney.de/pget.php?&tw=1&pmid=33290397 #FOAvip The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through 'repurposing' drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry. Twit Text FOAVip Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection ????PLoS Comput Biol http://www.kidney.de/pget.php?&tw=1&pmid=33290397 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33290397 #FOAvip English Wikipedia <ref>{{Cite pmid|33290397}}</ref> Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection #MMPMID33290397 Padmanabhan P; Desikan R; Dixit NM PLoS Comput Biol 2020[Dec]; 16 (12): e1008461 PMID33290397show ga The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through 'repurposing' drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry. |Animals[MESH] |COVID-19 Drug Treatment[MESH] |Cathepsin B/*chemistry[MESH] |Cathepsin L/*chemistry[MESH] |Chlorocebus aethiops[MESH] |Drug Repositioning[MESH] |Humans[MESH] |Models, Theoretical[MESH] |Protein Binding[MESH] |SARS-CoV-2/*physiology[MESH] |Serine Endopeptidases/*chemistry[MESH] |Spike Glycoprotein, Coronavirus/genetics[MESH] |Vero Cells[MESH] |Virion[MESH]Targeting TMPRSS2 and Cathepsin B/L together may be synergistic agains(epmc).pdf DeepDyve Pubget Overpricing