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How does VTose (DRACO) work?


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Let's start with how human cells normally defend themselves against viruses. One way this works is through antibodies. These large, Y-shaped proteins are produced by plasma B cells, a type of white blood cell. Antibodies attach to certain pathogens, effectively tagging them for further attack by the immune system. However, we only make antibodies after being exposed to a pathogen. If the pathogen mutates, or if you're exposed to a new one, antibodies won't work.

Another way our cells defend themselves is by using a certain protein (called Protein Kinase R) to identify the products of viruses inside our cells. When that happens, the cells produce Interferon, which signals the cell and its neighbors to reduce the rate at which they create new proteins. Doing that helps slow the virus down. In addition, cells also try to commit suicide, through a natural process called apoptosis.

Apoptosis results in a cell "imploding." By that I mean that it breaks into a number of small pieces, which can then be ingested, absorbed and destroyed by scavenger cells. You can see the small pieces in the images below of a cell undergoing apoptosis:

image.png.f66727e300e3b1e9c3db3ef4e386c7b7.png

An average human adult loses 50 to 70 billion cells to apoptosis every day. Those old or damaged cells are then simply replaced by new, healthy ones.

By contrast, in necrosis, the opposite of apoptosis, a cell's outer membrane breaks, and its interior just spills or "explodes" into the surrounding area. While apoptosis is considered normal by the immune system, necrosis generates all kinds of alarms ("danger signals"), resulting in inflammation and other actions by the immune system.

Unfortunately, viruses have also evolved a number of mechanisms that interfere with these defenses. For example, they can prevent Interferon from being created, or apoptosis from happening, or both.

The way VTose works is by providing a direct path from virus detection to apoptosis. Normally, there are multiple biochemical steps between virus detection and the apoptosis trigger. Viruses tend to interfere very early in that chain of events. In contrast, VTose triggers the process very late in the chain. By avoiding those first, early steps, there's very little the virus can do to defend itself.

The detection target and mechanism are actually the same one used by the body: (part of) the PKR protein attaches to long segments of double-stranded RNA (dsRNA), which are produced only by viruses, and not in healthy human cells.

To summarize, it works like this:

dsRNA --> detected and attached by VTose --> triggers activation of apoptosis --> cell death by "implosion" --> cell fragments are scavenged and removed

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Thank you for this summary!

Do you know yet how VTose will be metabolized if only a few infected cells are present (or, correspondingly, if a greater dose of VTose is taken in relation to the number of infected cells)? Does it remain in the body "waiting" for an infection, or is it metabolized and excreted quickly otherwise?

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12 hours ago, CarrieB said:

Thank you for this summary!

Do you know yet how VTose will be metabolized if only a few infected cells are present (or, correspondingly, if a greater dose of VTose is taken in relation to the number of infected cells)? Does it remain in the body "waiting" for an infection, or is it metabolized and excreted quickly otherwise?

VTose is a protein. During the prior testing, their version of the drug persisted in uninfected HeLa cells for up to 8 days. At some stage, it will decay and be catabolized like other cellular proteins (often due to thermal or enzymatic effects). While it's active, this residual suggests two possibilities: 1) some antiviral prophylactic effect may linger for multiple days after initial dosing, and 2) the dose required to treat an active infection may end up being relatively low. In fact, their effectiveness studies showed that only 10 nM/L is enough to be effective. That concentration is roughly on the order of some human hormones, which is very low compared to most drugs.

We also know that the transduction tags are pretty efficient at transporting the compound out of the plasma and into cells, both in the cytoplasm and the nucleus, and that their toxicity testing showed the compound to be almost completely non-toxic.

The prior work didn't look much at pharmacokinetics or pharmacodynamics. However, since the drug is a protein, my guess at the moment is that the amount that remains in the serum, outside of cells, could be quickly filtered out by the kidneys. PD and PK are on the list of subjects we will need to investigate prior to filing an IND.

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2 hours ago, Patrik said:

Interesting

Maybe you can use Dimethyl sulfoxide as a "delivery system" to cells (it can penetrate skin)...but maybe it dissolve the VTose protein 🙂

DMSO could well be an alternative to injection. It might also be useful for viral skin lesions, such as Herpes or Shingles.

For final delivery into cells, the current approach uses special "transduction tags." These are short sequences of amino acids at one end of our protein. Studies have shown these peptides encourage cells to "ingest" the entire protein, bringing it inside the cell, and even inside the nucleus. I don't know whether DMSO would work as an alternative to transduction tags, but it's certainly an idea worth exploring.

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41 minutes ago, Patrik said:

When VTose comes out, can everybody afford it ?

We don't have the staggeringly massive overhead of big pharma, and we're not interested in creating drugs which merely suppress viral infections for decades at a high monthly cost, as they are. It's too early to say what the ultimate cost can be, but - assuming, of course, proof of efficacy and safety in humans - we expect that it will be affordably priced for a large number of individuals.

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