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Denmark will start a clinical trial of a drug named camostat mesylate tomorrow—barely 1 month after a Cell paper showed the compound can prevent the novel coronavirus, SARS-CoV-2, from entering human cells...
The viral particle needs to enter the host cell in order to use the host’s replicative mechanism to divide and multiply so as to attack the host.
Camostat mesylate is already licensed in Japan and South Korea to treat pancreatitis, a potentially fatal inflammation of the pancreas.
Researchers around the world are investigating existing drugs as potential therapies for COVID-19, most of them looking at antivirals, such as remdesivir, developed to treat Ebola, or Kaletra, a combination drug against HIV.
However the virus can not replicate on its own. It needs our replicative mechanism to replicateCamostat mesylate is one of several candidate drugs that block those interactions. They don’t target the virus, but us, the host.
Decision to use this drugs was informed from the studying of the complicated molecular interactions that happens between a virus and its host cells.
For instance, from past work, researchers know in detail how other coronaviruses—those that cause severe acute respiratory syndrome and Middle East respiratory syndrome—infect a cell. First, a protein on the viral surface called the spike attaches to a receptor on the human cell
... called ACE2. Then, another human protein, TMPRSS2, cleaves the spike protein, allowing the virus to fuse with the cell and start to replicate inside it.
Camostat mesylate blocks TMPRSS2. In a Cell paper, molecular biologist Stefan Pöhlmann of the German Primate Center and other researchers showed the drug kept SARS-CoV-2 from infecting lung cells in the lab.
TMPRSS2’s normal role in the human body is unclear, Pöhlmann says. Knocking out the gene in mice seems to leave them unaffected.
In a preprint first posted on bioRxiv on 22 March, Krogan and a team of dozens of international presented their results: 332 human proteins that SARS-CoV-2 appears to target.
The virus gets its fingers in most of the major biological processes,including DNA replication, vesicle trafficking, and the cytoskeleton.
For many of the proteins, there is no clear explanation why the virus would need them. Some may simply be false hits. But many human proteins have several functions, not all of which are known.
They include camostat mesylate and a closely related compound called nafamostat that also acts on TMPRSS2 but is given intravenously. Another one is chloroquine (and its sister compound hydroxychloroquine), a drug that has garnered a lot of attention but its effectiveness...
Host-directed drugs are more likely to do harm than therapies because those drugs target the virus directly. In essence if you’re hitting a host target, hitting a host function, there’s an increased safety risk, hence there is hopes that focusing on drugs already approved for...
... other diseases, such as camostat mesylate, will largely bypass that problem.
On the other hand, the virus may be less likely to develop resistance to these therapies, because the targeted proteins are encoded in the human genome and not that of the virus.
On the other hand, the virus may be less likely to develop resistance to these therapies, because the targeted proteins are encoded in the human genome and not that of the virus.
If researchers manage to target a human protein that’s central in coronavirus infections in general, it could even lead to a broader therapeutic,then you would also have a treatment for subsequent COVID’s or whatever virus comes.
If any leads look promising in the lab, they could soon enter clinical trials as well. Of the 69 drugs, 27 are already approved, 14 are in clinical trials, and 28 are in preclinical tests. Most of the newly identified drugs will probably hinder the virus, says Stanley Perlman...
Perlman says combining such drugs with another type of host-directed treatment that dampens the immune system may be the way to go. That approach may sound paradoxical, but the immune system itself may cause much of the damage to the lungs of COVID-19 patients...
...as it fights the infection, says Susanne Herold, an expert on pulmonary infections at the University of Giessen in Germany. “If you knock down the virus without the host immune response, you may not change anything,” Perlman says.
“If you knock down the host immune response without the virus, you can enhance virus replication, which would be a problem.”
Researchers are looking at several compounds to lessen the immune response.
Researchers are looking at several compounds to lessen the immune response.
They are trying to find out, for instance, whether using antibodies to block interleukin 6 or complement component 5, two signaling molecules that play a role in the human immune defense, can help patients. The danger is that dampening the immune system could make patients...
... dampening the immune system could make patients susceptible for other infections, Herold notes—for instance bacterial infections of the lung.
Time will be our greatest bane if we should go through a Herculean task of developing a new drug for COVID-19, hence the use of existing drugs which have proven potent in solving similar conditions could be our only resort. @muss_tapha10 @__baffour @teigideongmail1 @estonia_borga
