COVID-19

Coronaviruses are a group of related viruses that cause diseases in mammals and birds. In humans, coronaviruses cause respiratory tract infections that can be mild, such as some cases of the common cold, and others that can be lethal, such as SARS, MERS, and COVID-19. Symptoms in other species vary: in chickens, they cause an upper respiratory tract disease, while in cows and pigs they cause diarrhea. There are yet to be vaccines or antiviral drugs to prevent or treat human coronavirus infections. Reverse engineering the Coronavirus

OPEN QUSTIONS

How is orf1ab cleaved into polypeptides? Can we predict this from the sequence?
How do the researchers know (guess?) where orf1ab cleaves?
    nsp3 and nsp5 do it -- https://www.pnas.org/content/pnas/103/15/5717.full.pdf
Which protein is the immune system responding to?
    "spike" and "nucleocapsid" -- http://www.cmi.ustc.edu.cn/1/3/193.pdf
    Are some people already immune from exposure to other coronavirus?
Find the "furin cleavage site" in the "spike glycoprotein"
    It might be at the "PRRA" -- https://www.sciencedirect.com/science/article/pii/S0166354220300528
    Use ProP or PiTou to predict? -- https://en.wikipedia.org/wiki/Furin
How similar are the other coronaviruses? (causes colds, not either SARS or MERS)
    alpha
        https://en.wikipedia.org/wiki/Human_coronavirus_229E (simpler, though targets APN)
        https://en.wikipedia.org/wiki/Human_coronavirus_NL63 (targets ACE2!)
            https://www.ncbi.nlm.nih.gov/nuccore/MG772808
    beta
        https://en.wikipedia.org/wiki/Human_coronavirus_OC43 (targets Neu5Ac)
            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095096/pdf/JIDMM17330.pdf
            Specifically, how similar is the N protein OC43, SARS v1, and SARS v2?
        https://en.wikipedia.org/wiki/Human_coronavirus_HKU1 (targets Neu5Ac)
        MERS-CoV
        SARS-CoV
        SARS-CoV-2
What adds the phosphate group to the N protein? Kinase?

Work to be done

Automatic extraction of genes from different coronaviruses
Good multisequence compare tool
Molecular dynamics?
Secondary Structure prediction on orf1a?

Homemade Vaccine

https://siasky.net/bACLKGmcmX4NCp47WwOOJf0lU666VLeT5HRWpWVtqZPjEA
Based on injecting DNA (plasmid) that expresses the spike protein

Bio vs IDA

Each letter in genome is a "byte at address x"
Translation = Disassembly, it's a 3 byte wide instruction set with arbitrary "reading frames"
Protein ~ Function. polyprotein = Function with multiple pieces
Proteins appear to have "basic blocks" = "Secondary Structure"
    80% accuracy in prediction: https://en.wikipedia.org/wiki/Protein_structure_prediction#Secondary_structure
"Tertiary Structure" forms a function
    This seems like the hard one to predict: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205819
"Quaternary Structure" is like compiled function with inlining
    https://en.wikipedia.org/wiki/Protein%E2%80%93protein_interaction_prediction
Gene ~ library (bacteria are static linked, viruses are dynamically linked)
Transcription = loading off disk

Analysis

There is no equivalent to execution, we are reverse engineering a CAD format
Static analysis, looking at the DNA, protein structure prediction, FLIRT signatures, etc...
Simulation doesn't seem to work yet
Tons of in system dynamic analysis, but the tools are crap
Runs more like FPGA code, all at once, no serial execution (what are the FPGA re tools?)

Tests (how they work)

All based on https://en.wikipedia.org/wiki/Reverse_transcription_polymerase_chain_reaction
USA -- https://www.fda.gov/media/134922/download
    selected from regions of the virus nucleocapsid (N) gene
    28286---28308--28332---28358
    29163---29187--29210---29230
    https://biosearchtech.a.bigcontent.io/v1/static/coa_KIT-NCOV-PP1-1000_Lot-No-143503
South Korea -- http://www.kogene.co.kr/eng/about_us/news/listbody.php?h_gcode=board&h_code=7&po_no=288
    E gene detection (same for all coronavirus)
    specific RdRp detection

Homemade test?

Isolation of viral RNA (no matter what)
    https://www.qiagen.com/us/products/diagnostics-and-clinical-research/sample-processing/qiaamp-viral-rna-mini-kit/#orderinginformation
Primers and probes (to detect SARS-CoV-2)
    https://www.biosearchtech.com/products/pcr-kits-and-reagents/pathogen-detection/2019-ncov-cdc-probe-and-primer-kit-for-sars-cov-2
    Wouldn't need if using a nanopore sequencer (nanopore MinION)
RT-qPCR Master Mix (to PCR)
    https://www.thermofisher.com/order/catalog/product/A15300#/A15300
    Probably wouldn't need if using a nanopore sequencer
All in one?
    https://www.chaibio.com/coronavirus
    Open qPCR, understand https://www.chaibio.com/openqpcr
    FAM and HEX fluorophores?

Treatments

Hydroxychloroquine + Zinc
    Zinc blocks RdRp
        https://jvi.asm.org/content/91/21/e00754-17 -- how similar is Hep E RdRp?
        https://www.ncbi.nlm.nih.gov/pubmed/21079686
    Chloroquine Is a Zinc Ionophore (allows zinc into the cell)
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/
Novel RdRp inhibitors
    Favipiravir (prodrug for favipiravir-RTP)
Adenosine Analog
    Remdesivir (prodrug for GS-441524)
    Galidesivir

Resources

corona
    Chapter 4 - Coronavirus Pathogenesis -- https://www.sciencedirect.com/science/article/pii/B9780123858856000092
    https://www.futuremedicine.com/doi/pdf/10.2217/fvl-2018-0008
textbooks
    Molecular Biology of the Cell
classes
    better tests - https://ocw.mit.edu/courses/biology/7-012-introduction-to-biology-fall-2004/index.htm
    suspected better lectures - https://ocw.mit.edu/courses/biology/7-014-introductory-biology-spring-2005/index.htm

viai957/COVID-19

COVID-19