Korean researchers have found that a pyronaridine/artesunate combination is effective in vitro at inhibiting replication of SARS-CoV-2.
They claim the effect is more potent than chloroquine!
Indeed, in malaria, pyronaridine does have a similar mechanism and greater potency--
They claim the effect is more potent than chloroquine!
Indeed, in malaria, pyronaridine does have a similar mechanism and greater potency--
I have not yet seen the paper, but based on evidence in malaria, I believe this is likely to hold up.
I am uncertain as to how much the artesunate component matters. It appears very likely that pyronaridine is the primary active component in this setting.
I am uncertain as to how much the artesunate component matters. It appears very likely that pyronaridine is the primary active component in this setting.
Archived copy of the media article announcing successful in vitro inhibition of SARS-CoV-2 replication by pyronaridine/artesunate combination:
archive.fo/Y4zWH
archive.fo/Y4zWH
Pyronaridine, chloroquine, and niclosamide work by preventing endosome acidification (necessary for viral membrane fusion).
Many common viruses, including influenzaviruses, rhinoviruses, and coronaviruses, can be blocked from replicating by this method.
journals.plos.org/plospathogens/…
Many common viruses, including influenzaviruses, rhinoviruses, and coronaviruses, can be blocked from replicating by this method.
journals.plos.org/plospathogens/…
Chloroquine and pyronaridine diffuse into the endosome, protons are pumped in as the cell prepares to turn it into an endolysosome, they get protonated, and they can't diffuse back out. pH remains stable instead of falling.
sciencedirect.com/topics/medicin…
ncbi.nlm.nih.gov/pmc/articles/P…
sciencedirect.com/topics/medicin…
ncbi.nlm.nih.gov/pmc/articles/P…
Niclosamide is a bit different-- it shuttles protons back across the endosome membrane instead.
Either way: without an acidic pH, the host cell's acid hydrolase proteases cannot cleave the Spike protein, which means it cannot deploy the fusion peptide.
ncbi.nlm.nih.gov/pmc/articles/P…
Either way: without an acidic pH, the host cell's acid hydrolase proteases cannot cleave the Spike protein, which means it cannot deploy the fusion peptide.
ncbi.nlm.nih.gov/pmc/articles/P…
Such viruses hijack endocytosis by escaping endosomes as the contents are degraded by enzymes after lysosomal fusion to endolysosomes.
At neutral pH, the contents are not cleaved as expected. The still intact virus is dumped back outside by exocytosis.
jcs.biologists.org/content/131/15…
At neutral pH, the contents are not cleaved as expected. The still intact virus is dumped back outside by exocytosis.
jcs.biologists.org/content/131/15…
Eventually, it gets cleaned up by the immune system.
Antivirals inhibiting endosome acidification do not directly destroy viruses. They mainly just impair their replication.
The host immune system is still responsible for cleaning up free virions and already-infected cells.
Antivirals inhibiting endosome acidification do not directly destroy viruses. They mainly just impair their replication.
The host immune system is still responsible for cleaning up free virions and already-infected cells.
Interestingly, this class of antimalarials also has some potential value in cancer treatment, by preventing local acidification of the extracellular environment-- which is associated with proliferation, angiogenesis, invasion, and resistance to apoptosis.
onlinelibrary.wiley.com/doi/abs/10.100…
onlinelibrary.wiley.com/doi/abs/10.100…
Mitochondria also maintain proton gradients-- and chloroquine, pyronaridine, and especially niclosamide and nitazoxanide are weak mitochondrial uncouplers.
The latter can subtly increase body temperature and metabolic inefficiency at high doses.
They also kill cancer cells.
The latter can subtly increase body temperature and metabolic inefficiency at high doses.
They also kill cancer cells.
Note the mention of salinomycin in the first image.
Salinomycin is also a proton ionophore, and hence disrupts endosome acidification.
Accordingly, it likewise has broad-spectrum antiviral and oncocidal properties.
ncbi.nlm.nih.gov/pmc/articles/P…
ncbi.nlm.nih.gov/pmc/articles/P…
Salinomycin is also a proton ionophore, and hence disrupts endosome acidification.
Accordingly, it likewise has broad-spectrum antiviral and oncocidal properties.
ncbi.nlm.nih.gov/pmc/articles/P…
ncbi.nlm.nih.gov/pmc/articles/P…
Monensin, an anticoccidial used in agriculture like salinomycin, is likewise a hydrogen ionophore.
It has also appeared in high-throughput screening against coronavirus replication, alongside e.g. salinomycin and chloroquine--
ncbi.nlm.nih.gov/pmc/articles/P…
ncbi.nlm.nih.gov/pmc/articles/P…
It has also appeared in high-throughput screening against coronavirus replication, alongside e.g. salinomycin and chloroquine--
ncbi.nlm.nih.gov/pmc/articles/P…
ncbi.nlm.nih.gov/pmc/articles/P…
Proton ionophores are useful drugs: against many different viruses, malaria parasites, coccidia parasites, tumor cells, and cancer stem cells.
They work by disrupting proton gradients inside organelles within cells.
Zinc has very little to do with it.
They work by disrupting proton gradients inside organelles within cells.
Zinc has very little to do with it.
Broad-spectrum antivirals do exist, and you are looking at an important class of them right now.
The claim that there is no specific treatment for the common cold, for instance, is a complete lie.
These are effective against rhinoviruses, coronaviruses, and many others.
The claim that there is no specific treatment for the common cold, for instance, is a complete lie.
These are effective against rhinoviruses, coronaviruses, and many others.
I would also argue that, as a general matter, combinatorial chemotherapy is still grossly underused in the treatment of cancer and often applied far too late in the clinical course-- but that is an entirely separate discussion, too complex to address here.
