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Nevan @KroganLab up now: >40 labs at QBI joined to form QCRG (QBI Coronavirus Research Group at UCSF https://qbi.ucsf.edu/QCRG/overview ), collaborating with groups around the world aiming for pan-pathogenic strategies (for "COVID-21, COVID-22, …")
Identified 66 druggable targets/69 drugs https://twitter.com/HarvardDBMI/status/1328726322470907904
Identified 66 druggable targets/69 drugs https://twitter.com/HarvardDBMI/status/1328726322470907904
A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing https://www.nature.com/articles/s41586-020-2286-9– high-confidence human PPI map
– plasmids to 378 labs in 42 countries
– http://ppi.zoiclabs.io was made by a film co (who connected via Twitter's @biz) ! https://twitter.com/biochemistries/status/1291767065381150720
Initially (with collaborators at Pasteur & Mt Sinai) used Vero6 green monkey cell lines and plaque assays, now using human lines, tested 2/3 of candidates
10 agents showing efficacy:
Protein translation/biogenesis inhibitors: zotatifin, & ternatin-4/plitidepsin (inhibits eIF1a)
10 agents showing efficacy:
Protein translation/biogenesis inhibitors: zotatifin, & ternatin-4/plitidepsin (inhibits eIF1a)
…plus several putative/known SigmaR1/SigmaR2 modulators:
- Antihistamines (cloperastine, clemastine)
- Antipsychotics (haloperidol, melperone)
- Antimalarials (HCQ)
- Hormone (progesterone)
- Antianxiety (siramesine)
- Preclinical (PB28 and PD-144418)
- Antihistamines (cloperastine, clemastine)
- Antipsychotics (haloperidol, melperone)
- Antimalarials (HCQ)
- Hormone (progesterone)
- Antianxiety (siramesine)
- Preclinical (PB28 and PD-144418)
Next #phosphoproteomics
The Global Phosphorylation Landscape of SARS-CoV-2 Infection https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4
Predicting kinases misregulated w @pedrobeltrao (10% of 500 kinases up/downregulated in COVID)
Kevan Shokat "has the biggest freezer of kinase inhibitors in the world"
The Global Phosphorylation Landscape of SARS-CoV-2 Infection https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4Predicting kinases misregulated w @pedrobeltrao (10% of 500 kinases up/downregulated in COVID)
Kevan Shokat "has the biggest freezer of kinase inhibitors in the world"
Genetic validation of pharmacological inhibition of p38 pathway, a number of cancer pharmas now segueing to COVID pharms
Looked at filopodia formation with Elizabeth Fischer & Robert Grosse: actin-like protrusions in infected cells: virus infects other cells independent of ACE2
Looked at filopodia formation with Elizabeth Fischer & Robert Grosse: actin-like protrusions in infected cells: virus infects other cells independent of ACE2
Working model: a couple of viral proteins are hijacking pathways (casein kinase 2) involved in cytoskeletal formation so virus can transfer cell-cell more efficiently. Also Nsp7 manipulating another pathway involving Rho
Lot of lovely/creepy tentacle EM pics by Elizabeth Fischer
Lot of lovely/creepy tentacle EM pics by Elizabeth Fischer
San Fran Chronicle asked for a list of 10 most promising compounds, 7 of 10 now in clinical trials. Aplidin is eIF1A inhib, used in myeloma by Spanish co PharmaMar
HEK293T-ACE2 cells show aplidin 30x more potent than remdesivir (in mice)
Work by Kris White & Adolfo Garcia-Sastre
HEK293T-ACE2 cells show aplidin 30x more potent than remdesivir (in mice)
Work by Kris White & Adolfo Garcia-Sastre
(Not sure if it's this https://www.sfchronicle.com/bayarea/article/How-a-UCSF-lab-took-on-the-global-race-to-block-15238219.php or this https://www.sfchronicle.com/health/article/UCSF-led-researchers-dig-deep-into-coronavirus-15648808.php story mentioned)
Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms https://science.sciencemag.org/content/early/2020/10/14/science.abe9403.fullCloned CoV-1/2, MERS proteins, transient transfections & microscopy to determine organelle localisation, parallel PPI map to be combined w functional analysis
Orf9b exists with SARS-CoV-1/2 but not MERS, localises ("quintessentially") to mitochondria
Genetically validated with siRNA knockdowns in A459-ACE2, and CRISPR knockouts in Caco-2
73 genes genetically confirmed out of 332 interacting human proteins
Many other screens (~5)
Genetically validated with siRNA knockdowns in A459-ACE2, and CRISPR knockouts in Caco-2 73 genes genetically confirmed out of 332 interacting human proteinsMany other screens (~5)
ORF9b found physically associated with TOMM70, mitochondrial chaperone (so consistent with localisation)
QCRG struct. bio. consortium (led by Rosenberg & Verba), ~60 students/postdocs set up biochem/struct.bio pipelines to validate in 18 different labs: got CryoEM of Tom70-Orf9b
QCRG struct. bio. consortium (led by Rosenberg & Verba), ~60 students/postdocs set up biochem/struct.bio pipelines to validate in 18 different labs: got CryoEM of Tom70-Orf9b
Sites highly phosphorylated in infection are inhibiting this interaction, suggests that separating this complex can help fight the virus
Orf9b "shape shifter": potentially key node for SARS-CoV-1, 2, and [potentially future] "SARS-CoV-3"
Orf9b "shape shifter": potentially key node for SARS-CoV-1, 2, and [potentially future] "SARS-CoV-3"
An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike https://science.sciencemag.org/content/early/2020/11/04/science.abe3255.fullBi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike https://www.biorxiv.org/content/10.1101/2020.08.08.242511v1
