c19early.org
COVID-19 Treatment Clinical Evidence
COVID-19 involves the interplay of 500+ viral and host proteins and factors, providing many therapeutic targets.
c19early analyzes 6,000+ studies for 220+ treatments—over 17 million hours of research.
Only three high-profit early treatments are approved in the US.
In reality, many treatments reduce risk,
with 26 low-cost treatments approved across 163 countries.
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Naso/
oropharyngeal treatment Effective Treatment directly to the primary source of initial infection. -
Healthy lifestyles Protective Exercise, sunlight, a healthy diet, and good sleep all reduce risk.
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Immune support Effective Vitamins A, C, D, and zinc show reduced risk, as with other viruses.
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Thermotherapy Effective Methods for increasing internal body temperature, enhancing immune system function.
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Systemic agents Effective Many systemic agents reduce risk, and may be required when infection progresses.
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High-profit systemic agents Conditional Effective, but with greater access and cost barriers.
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Monoclonal antibodies Limited Utility Effective but rarely used—high cost, variant dependence, IV/SC admin.
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Acetaminophen Harmful Increased risk of severe outcomes and mortality.
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Remdesivir Harmful Increased mortality with longer followup. Increased kidney and liver injury, cardiac disorders.
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SARS-CoV-2 main protease inhibition through dimerization promotion by peptidomimetic inhibitors and disruption by ebselen,
eLife,
doi:10.7554/eLife.109956
The SARS-CoV-2 main protease (M pro ) is a key antiviral target that equilibrates between an active dimer and inactive monomer, making the dimerization interface a promising therapeutic vulnerability. This study investigates M pro monomer-dimer equilibrium and conformational changes induced by inhibitor binding using 13 C labeling with native mass spectrometry and hydrogen/deuterium exchange mass spectrometry (HDX-MS). We evaluated how peptidomimetic inhibitors (PF-07321332, PF-00835231, GC376, boceprevir) and non-peptidomimetic inhibitors (carmofur, ebselen, MR6-31-2, AT7519, pelitinib) influence M pro dimerization and subunit exchange. Key findings revealed divergent mechanisms: peptidomimetic inhibitors significantly shifted the equilibrium towards the dimeric state, suppressing subunit exchange dynamics and rigidifying the dimer interface; in contrast, ebselen impaired dimer formation and increased interface flexibility. Notably, tandem mass spectrometry identified a novel covalent binding site for ebselen at C300. Molecular dynamics simulations and mutational analyses demonstrated that this C300 modification allosterically alters the hydrogen bond network of the dimer interface, directly contributing to ebselen-mediated dimer disruption and enzymatic inhibition. Overall, this study clarifies distinct inhibitory modes between peptidomimetics and ebselen, highlighting the therapeutic potential of targeting allosteric sites at the dimer interface for designing next-generation M pro inhibitors.