Friday, March 13. 5:00 a.m. The alarm clock rings. I check my email while drinking my coffee. My stock portfolio lost 22% of its value the day before. The communal swimming pool wrote to tell me to stay at home this morning: the area will be closed until April 3rd.
I'm going to the supermarket. The place is overcrowded. There's almost no pasta, no rice or toilet paper on the shelves. Parents wear masks and babies’ carriages are covered with large sheets.
Coronavirus is contagious, but panic is even more so.
I get in line for the cash register. I have time to count 23 people ahead of me. It lets me time to think. The old lady behind me compares the situation to a war period; I'm listening to her with a distracted ear.
I’m busy mentally scrolling scientific articles I read in the past ten days. The strategies biotech companies intend to develop to tackle the outbreak might be my next article…
2019-nCoV infects the human respiratory epithelial cells: indeed, the spike protein (S) of the virus binds with on human ACE2 receptors and uses the cellular protease TMPRSS2 for its activation. You can then choose between blocking the receptor via monoclonal antibody (1), inhibiting TMPRSS2 (2), competing for the ACE receptor with a soluble form (3), or destabilizing the fusion of lipid-enveloped virus with cellular membrane (4).
1. Blocking the ACE2 receptor on epithelial cells with mAbs
- Regeneron is exploring the potential of REGN3048 and REGN3051 monoclonal antibodies
- Vir Biotechnology & WuXi announced partnership for monoclonal antibodies development
2. Inhibiting TMPRSS2
- Approved drug camostat mesilate (FOY 305, from ONO)
3. Competing for the receptor with a soluble form
- APEIRON Biologics develops APN01, a recombinant human angiotensin converting enzyme 2 (rhACE2).
4. Inhibiting membrane fusion process
- NanoViricides: when the virus comes in contact with the nanoviricide, the nanomicelle polymer is designed to fuse with the virus lipid envelope.
- Pharmstandard and its Arbidol
- Innovation Pharmaceuticals focus on antimicrobial peptides (AMPs), also called host defense peptides (HDPs), and named its compound Brilacidin.
After infecting human lungs, coronavirus causes an influx of macrophages and immune cells, and so related cytokines. Immunosuppression (5) and immunomodulation (6) approaches are currently investigated.
5. Inhibiting inflammatory response
- InflaRx bet on its anti-C5a monoclonal antibody targeting the complement
- Roche prefers to push its anti-IL6 humanized monoclonal antibody (tocilizumab) since this IL6 is known to be proinflammatory.
6. Immunomodulation
- Heat biologics elicits cell response thanks to its engineered form of the heat shock protein (HCP), gp96.
- Cytodin developed an anti-CCR5 humanized IgG4 mAb (leronlimab).
Deaths caused by COVID-19 infection are mostly a result of acute respiratory distress syndrome (ARDS). To rapidly address this condition, increasing the oxygenation in cells might be a first-aid act.
7. Balancing of the ventilation/perfusion ratio, reducing hypoxemia and respiratory distress
- Mallinckrodt and its nitric oxide (iNO)
- Bioxytran and BTX-25, a hybrid glycopolymer made of HEME structure and a proprietary polymer chemical structure.
- Algernon Pharmaceuticals: would like to prove that NP-120 (Ifenprofil) could play a role for coronavirus treatment by inhibiting NDMA receptors
A different strategy could be to induce a protective immune response in humans.
Polyclonal antibodies and vaccines should do the job, respectively as passive (8) and active (9) immunotherapy treatment.
8. Actively creating a protective immune response with active plasma-derived components: a patient-to-patient immunity transfusion approach, whose polyclonal immunoglobulins are the key players
- Takeda Pharma
- Kamada
- Emergent
9. Proactively induce a protective immune response by mimicking the natural interaction of the infection with our immune system: the vaccine strategy against the viral membrane proteins of the virus
9.1. DNA Vaccine
- Inovio with plasmid DNA INO-4800 & INO-4700
- Applied DNA Sciences and Takis Biotech: linear DNA vaccine
- Zydus Cadila
9.2. Live-attenuated strain vaccine
- Serum Institute & Codagenix
9.3. Mucosal Vaccines
- Altimmune thanks to intranasal mucosal strategy
- Vaxart oral vaccine
- MIGAL Research Institute
9.4. mRNA vaccine
- Pfizer & BioNtech collaboration
- Moderna: mRNA-1273
- CureVac & CEPI agreement
9.5. Viral vector vaccine
- Tonix Pharmaceuticals and its TNX-1800 horsepox viral vector from
- Zydus Cadila and its recombinant measles virus (rMV) vectored vaccine
9.6. Protein vaccine
- Novavax: Recombinant protein nanoparticles
- Clover & GSK: Recombinant subunit trimeric S protein (S-Trimer)
- AJ Vaccine: viral subunits
- CEL-SCI: Peptide vaccine from LEAPS platform
- Generex: Peptide vaccine
To tackle coronavirus, some players prefer to work on strategies at the gene level. Old strategies that have proven effective on other viruses like inhibiting replication of HIV and Influenza could also be an option for COVID-19 (10). A more recent approach would be to tackle virus mRNA translation thanks to siRNA (11).
10. Inhibiting RNA polymerase to block viral replication: small molecule antiviral therapeutics made their comeback
- Gilead Sciences: GS-5734 (remdesivir) is a novel antiviral drug which contain a nucleic acid analogue, and phosphate groups. Once phosphorylated, they becale similar enough to nucleosides to be integrated into the replicating strands of viral DNA, but they act as chain terminating agents and stop the action of the viral DNA polymerase.
- Pfizer is working on the same approach as Gilead.
- Biocryst Pharma: BCX4439 (Galidesivir) : RNA polymerase inhibitor
- Zhejiang Hisun Pharmaceutical: RNA polymerase inhibitor
11. Gene silencing siRNA to prevent viral mRNA translation
- Alnylam & Vir Biotechnology: Small interfering RNA (siRNA), sometimes referred as silencing RNA, interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation.
CONCLUSION
Coronavirus treatment approaches are very diverse and are a pretty good representation of the breadth of our knowledge in biotechnology. They are the opportunity to reconnecting with the past by repurposing a drug, to validate a new technical platform, or to expand our knowledge of certain compounds under development.
