We are moving fast towards deploying labs to Fight the Coronavirus with Eterna. An immediate question is: what should be the first proteins whose mRNA we will stabilize against degradation? Developers have thoughts but cannot scour the emerging literature as quickly as the player community. Please post your ideas and analyses in this thread.
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You said over at the Fight the COVID-19 with Eterna post:
âTo start, we will be looking to design mRNAs for some âclassicâ test proteins like GFP and/or luciferase but we also want to include at least one antigen, even in the first round, that could immediate convert into a vaccine.â
An antigen is an antibody. Here are some intros to the topic antigens:
My own personal favorite for an antigen/antibody, is one for the nucleocapsid protein of coronavirus.
The nucleocapsid is the protein that is holding the RNA inside the virus capsule.
I have read that antibodies have before been used against nucleocapsid proteins in a virus:
âNaproxen, a non-steroidal anti-inflammatory drug, has previously been revealed to exert antiviral activity against influenza A virus by impeding nucleoprotein (NP) binding to RNA in a study by Nathalie Lejal et al [2].â Response to the emerging novel coronavirus outbreak
One advantage of targeting the nucleocapsid is that it is highly conserved. Plus the virus canât get packaged, without its nucleocapsid proteins.
DETECTION OF THE NEW CORONAVIRUS DISEASE 2019 (COVID-19) BY RAPID SERODIAGNOSTIC ASSAYS
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Copper is viricidal.
Copper Complexes of Non-Steroidal Anti-Inflammatory Medicines.
https://pdfs.semanticscholar.org/5f45/326721160bf418b463f4a6cce0508fe6c48f.pdf
Antiviral Activities of Cu2+Ions in Viral Prevention, Replication, RNA Degradation, and for Antiviral Efficacies of Lytic Virus, ROS-Mediated Virus, Copper Chelation http://www.worldscientificnews.com/wp-content/uploads/2018/04/WSN-99-2018-148-168.pdf
So, copper complexed drugs might be considered like copperaspirinate, copperparacetamol, copperascorbate, etc.
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My best CoVid-19 SARS-CoV2 prospect. It comes from the C-terminal of the (envelope)E-protein. It is a reverse read [LDPVG]of the original peptide fragment. SwissTargetPrediction software http://www.swisstargetprediction.ch/ allows input as peptide, SMILES, or drawn figure. Similar 3D & 2D structures can be found for each target hit.
This peptide needs to be Docked against various targets [I donât do that].
The larger study from which the above hit came:
The most promising therapeutic is Remdesivir. It is delivered by IV transfusion and does not require refrigeration. The only RNA vaccine Iâve read about is the Moderna one. It does appear to require refrigeration, so that might be a good one to try. Which classes of vaccines should we be considering?
Just came across this article mentioning two German companies-CureVac and BioNTech-that I believe are working on Sars-CoV-2 vaccines. https://www.phgfoundation.org/briefing/rna-vaccines
Could we design an mRNA with the same codon that makes the outer coating of the virion and introduce the mRNA into a ribosome? The intent would be to produce an anti- trojan horse. It looks like the virion, but with nothing harmful inside. The immune system would produce antibodies that would stick to our designer protein and also to the CV-19 virion?
Modified_cyclodextrins_as_broad-spectrum_antivirals.
Note the beta-cyclodextrin found and the âdangling baitsâ.
Superficially resembles the coronavirus enemy too.
Cinanserin Is an Inhibitor of the 3C-Like Proteinase of SARS-CoV
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1112131/pdf/2484-04.pdf
SARS-CoV-2 Cell Entry Depends on ACE2 andTMPRSS2âŠ
https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2930229-4
Both BioNTech and CureVac recently started working on mRNA vaccines but I donât believe they have released a formulation.
REVIEW Open Access Corona virus envelope protein: current knowledge 2019 https://virologyj.biomedcentral.com/track/pdf/10.1186/s12985-019-1182-0
NSP5 required for replication:
STRUCTURAL DETERMINANTS OF CORONAVIRUS NSP5 FUNCTION AND INHIBITION https://etd.library.vanderbilt.edu/available/etd-07292014-133456/unrestricted/Maxwell.pdf
Structural Basis of Inhibition Specificities of 3C and3C-like Proteases by Zinc-coordinating and Peptidomimetic Compounds
https://www.jbc.org/content/284/12/7646.full.pdf+html
maybe copper-coordination too?
뱉Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.9b01828
@DigitalEmbrace have these companies disclosed what buffers and lipids they are mixing the RNA with for storage and for delivery by injection?
Letâs focus on a vaccine. That means we design an mRNA for a *virus protein* or virus protein chunk that, when expressed in our human bodies, will teach our immune systems to go after the real virus if they see it. So letâs move discussion of small molecule drugs, which will not be vaccines but are still important, back to the main thread.
It also means that, for a vaccine, we should probably focus on proteins or protein segments that are on the *outside* of the virion. (The virion is the state of the virus when its outside our cells and looking to infect them.) So our immune cells can be trained to see the virus before it gets into our cells. That may rule out nucleocapsid protein which is hidden inside the virion, though again that may be useful for thinking about other antiviral, non-vaccine efforts. @eli can you include a link here to material that you have found useful for the anatomy of the virus and which will explain what proteins would be on the the outside?
@eternacac, do your candidates involve protein segments that are accessible on the outside of the virion?
@rhiju, here is the link to what I have collected on the anatomy of the corona virus plus more.
Note my prospective peptide above has cathespin-L activity as a target, though not optimized for it.(see below)
Inhibitors of cathepsin-L prevent severe acute respiratory syndrome coronavirus entry https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188015/pdf/pnas-0505577102.pdf
TMPRSS2 activates the human coronavirus 229E for cathepsin-independent host cell entry and is expressed in viral target cells in the respiratory epithelium.
https://www.ncbi.nlm.nih.gov/pubmed/23536651
The Spike Protein of the Emerging Betacoronavirus EMC Uses a Novel Coronavirus Receptor for Entry, Can Be Activated by TMPRSS2, and Is Targeted by Neutralizing Antibodies https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648152/
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So another peptide:
PDLLV with these target hits of known interest in COVID-19 SARS-CoV2:
FOS-JUN, CASP8, HLA-DBR3, ACE, DPP4, CTSL, FURIN, AGTR1, HSP90AA1&AB1, PPARG and many others likely. Thatâs a lot of potential interference in Viral activity.
SwissTargetPrediction (display all)
http://www.swisstargetprediction.ch/result.php?job=1525274037&organism=Homo_sapiens
PDLLV - peptide from C-terminus E-protein SARS-CoV2
smiles: [H]N1CCC[C@H]1C(=O)NC@@HC(=O)NC@@HC(=O)NC@@HC(=O)NC@@HC(O)=O
Here is the drug trial for Moderna: https://clinicaltrials.gov/ct2/show/NCT04283461
It is quite likely the other two companies working on mRNA vaccines have not even defined their formulation yet.