It is likely that treatment for COVID will be based either on polymerase inhibitors (nucleoside-like or helicase inhibitors) and or protease inhibitors, most likely directed against the major viral protease (Mpro or 3CLpro). Other possibilities at the viral side would include monoclonal antibodies against the spike or other entry inhibitors. At the human side, active research is targeting the human proteases that have a role in the spike activation i.e. furin and TMPRSS2 and also the selective ACE2 receptor targeting could be considered.
In this episode, I’m focusing on the former two.
- One research line tries to apply molecules, previously developed for treatment of Feline Infectious Peritonitis Virus (FIPV). As you can read in https://www.vet.cornell.edu/departments-centers-and-institutes/cornell-feline-health-center/health-information/feline-health-topics/feline-infectious-peritonitis and in the first attachment, this alpha coronavirus virus can either cause benign gastro-enteritis or, after spontaneous mutation give rise to a systemic inflammatory disease, with severe neurological involvement. The next two papers show results of a protease inhibitor GC376 and a nucleoside analogue GS-441524 in symptomatic domestic cats with FIPV.
- The protease inhibitor was very efficient at suppressing the peripheral viral load (Fig 8 p.15), but nevertheless many animal relapsed. The explanation was not resistance, but poor penetration in CSF.
- The nucleoside analogue GS-441524 showed a better profile, but this time the authors had taken advantage of their experience with the protease inhibitor and had extended the treatment.
- In the fourth attachment, you can see that the same protease inhibitor GC376 is active against SARS-CoV-2 in vitro with an EC50 of about 1 micromolar and a favorable in vitro therapeutic index of > 200.
- Remarkably GS-441524 is a metabolic by-product of Remdesivir, which is excreted through the kidney (and thus could accumulate in renal failure). It has also a much higher concentration than Remdesivir in CSF, which might be a favorable characteristic in case of neurological involvement. See attachment 4 and 5.
- Besides these candidates, a lot of modeling is ongoing:
- An exercise by Iftikhar et al. explored a largely FDA approved library for docking in the viral enzymes and exclusion of non-specific interaction, resulting in 6 potential candidates:
- Rimantadine (anti-flu); Bagrosin (anti-epileptic) and Grazoprevir (anti- hepC protease NS3-4A) are potential 3CLpro (SARS-CoV-2 protease) inhibitors
- Casopitant, neurokinin-1 receptor antagonist (anti-nausea) as a potential RNA-dependent RNA polymerase (RdRp) antagonist
- Meclonazepam (sedative) and Oxiphenisatin are potential helicase inhibitors
- Another argument to test inhibitors of HCV NS3/4A Proteases as potential anti-SARS-CoV2 protease is the structural similarity between both (see Bafna et al) See 10.26434/chemrxiv.12153615
- With regard to vaccine development:
- An overview of today in Nature Briefings shows that over 320 candidates have been registered, of which 32 in clinical phase, of which 6 in phase III. Suppl Table 1 shows the 32 with in phase III the Adeno (Oxford/Astra-Zenica and Russian); 2 RNA (Moderna and BioNTech) and 2 inactivated (Wuhan and SinoVac). Clearly most target spike, but some also other proteins (e.g. N), evident also for the inactivated.
- An interview by Jon Cohen of an “old acquaintance” Monsef Slaoui, former head of Vaccine Development of GSK in Rixensart, now heading the “Operation Warp Speed”, the 10 billion dollar initiative, promoted by …. DJ Trump, to “deliver a COVID-vaccine before November”, in order to assure his re-election…… To quote our favored twitterer “We’ll see what’s happens”.
- On a more serious note, the FDA guidelines for COVID vaccine development. . According to the FDA: “Although establishing vaccine safety and efficacy in SARS-CoV-2 naïve individuals is critical, vaccine safety and COVID-19 outcomes in individuals with prior SARS-CoV-2 infection, which might have been asymptomatic, is also important to examine because pre-vaccination screening for prior infection is unlikely to occur in practice with the deployment of licensed COVID-19 vaccines. Therefore, COVID-19 vaccine trials need not screen for or exclude participants with history or laboratory evidence of prior SARS-CoV-2 infection. However, individuals with acute COVID-19 (or other acute infectious illness) should be excluded from COVID-19 vaccine trials.”
Comment by one of the colleagues: Thus: people with past COVID infection might be included, without knowing their status. Is that not creating a hazard of e.g. antibody-dependent enhancement and similar inflammatory risks?
On the same page, it becomes evident that FDA encourages the early inclusion of groups, traditionally excluded from the first phase 3 trials, including pregnant women, children, minorities etc.
In addition, it is not clear whether protection against infection or against disease will be the primary endpoint. Both seem fine.
My comments: All of a sudden, everything that was not possible until now, is fine. Officials are insisting that all the standard guarantees will be respected, despite the rush, the multiple parallel trials, the hunt for suitable populations
Obviously, political ambitions and public opinion pressure are playing a role. Keep fingers crossed….
26 August Genetic susceptibility, immunology, review on rapid tests and provocative interview
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18 August More on pregnancy, lingering viruses, mental health, collateral damage and children
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