Zika virus, its been a hot topic of discussion recently due to its rapid spread and potentially awful ramifications for pregnant women and their growing babies. As a result, research is in high gear in an attempt to find a way to combat the infection. Today we will be "briefly" discussing some new research published in the journal Nature Communications titled "A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses.". Here the authors describe their work on a small protein (peptide) that inhibits the viral growth of the Zika virus through busting apart its viral membrane! Lets dive on in!

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Zika Virus... Briefly

Zika is a member of the Flaviviridae family of viruses and is spread to humans by mosquitoes. The Flavviridae family is actually quite famous and you may be familiar with some of its brethren like: the west nile virus or Dengue virus or even Hepatitis... not a friendly bunch. Now the disease "Zika fever" is actually pretty mild (for an adult) and causes some inflammation, swelling, a fever, aches that sort of thing. The issue with it, is a little different if say.. a pregnant mother gets infected. Now in this case the virus can infect the fetus and the resulting Zika fever can lead to poor brain development (a condition called microencephaly), which has other side effects which include things like seizures, a messed up face (the scientific term of course), intellectual disabilities, and junky motor functions (difficulties moving around). This is certainly not a disease anyone of us would wish on an expectant mother. Having a baby is supposed to be a time of joy, not worry over the complications of a zika viral infection.

Are There Any Treatments?

Nope, there are currently no vaccines or other therapies available for the treatment of this infection.

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How About This Paper You Mentioned Above?

Oh yeah, that! So the researchers here were working on a small peptide which they named Z2. Now a peptide is just a very short protein, and if you recall from one of my posts from wayyyyy back in the stone age, a protein is a biological polymer composed of subunits called amino acids. So this peptide is really just a short chain of amino acids (not long enough to be called a protein).

What is soooooooo special about Z2?

Well I am glad you asked (and I appreciate the sarcastic tone!). If you are reading this and you would like to receive a prize of 4 SBD, please be the FIRST person to respond with the following statement in the comments. "My arms are pure Zika virus, and I'm not afraid to use them! Watch out everyone!"

You see the Z2 peptide was artificially made to have a special function, it mimics a portion of a protein in the viruses outer shell named the E Protein (wow guys... just wow.. E Protein? Seriously? Gotta find some more creative names then that!). The E protein exists normally in a pair of two (called a dimer... it interacts with itself) however when the virus fuses with the cell membrane of its host (in order to infect that cell) the pH around it gets very acidic. This results in the E protein changing from that dimer pair, to a group of three called a tetramer. [2.

This tetramer formation process involves that region of the protein that the Z2 peptide was designed to mimic. So if their is say... a bunch of that Z2 peptide around because you are oh I don't know.. taking it as a drug. Then when the virus goes to infect a cell instead of this tetramer forming in its outer shell, it will be missing a piece (which had its place taken by the Z2 peptide). This would put a bunch of holes in the virus and should lead to its genome... falling out! HAHA take that you stupid virus!

So How Did It Go?

Well they made two peptides, one mimicking the region of the E protein and another that has the same amino acids, only the sequence is all scrambled up (its called Z2-scrambled). They then took some cells in this case BHK21 (baby hamster kidney) or Vero (more kidney cells, only this time from a monkey!) and gave them varrying amounts of the peptides, then they infected the cells with Zika, and measured how many got infected.

Figure 1

So here we are looking at a plot of the amount of cells that DIDN'T get infected (higher is better). The blue dots (and lines) represent cells of the two classes that were given the scrambled Z2 (so not the right sequence to match up and disrupt that tetramer formation). We can see there that pretty much all of the cells were getting infected by zika virus (damn). The red dots (and lines) are the data from cells that were supplied the Z2 peptide, here we see that as the concentration of the peptide increases, less and less cells are able to get infected with the virus (hell yeah!).

• They also found that the peptide was able to inhibit the ability of the zika virus to infect the cells as soon as 2 hours after it infected. Which was a sign to the researchers that it was actually stopping the virus from getting into the cells.

The Peptide Stops The Viral Infection But Isn't Toxic To The Cells

So its good that it seems to work, but does the protein kill the cells?

Supplemental Figure 7

Above is a plot looking at three different cell types, and along the x-axis we have concentrations of the Z2 peptide. You can see pretty clearly that the amount of cells that continue to live after being administered even very high concentrations of the peptide (50 micro molar is a lot, much higher then they needed to stop the infectivity of the virus). So that's another good sign. Peptide looks like it works, and doesn't seem to harm the cells.

Can The Peptide Get To A Fetus?

So the next question is whether or not this peptide can make it to a fetus, since that's what we need to protect. Its the baby that has all of the health consequences of this virus. So this potential therapy needs to be able to make it to the baby to protect them from the virus or this is all moot! So the researchers tried to monitor where the peptide went in some pregnant mice, they wanted to see whether it could get into the mouse fetus.

Figure 4

So they tagged the peptide with a small fluorescent molecule, gave it to some mice, and then blasted them with light to see whether they would glow appropriately. The fluorescence emission of the peptide from the mice is shown above. On the left we have the fluorescent Z2 being administered and on the right a salty buffer (it's some phosphate, some sodium chloride and some potassium chloride) Okay good, the fluorescent peptide is able to be seen in the mice (you can see the colorful regions in the mice on the left). But where specifically is the light being detected from?

Figure 4

How about some fetuses? Heck yeah, the compound appears to be able to pass the placenta and make it to a fetus. So that's another positive check in its potential usefulness to protect the fetus from the virus!

Does The Peptide Harm The Growing Fetus?

Figure 5

Here the researchers were monitoring the growth weight of fetuses by day with increasing amounts of the Z2 peptide. You can see that increased amounts of the peptide don't do anything to the weights of the growing baby mice. The researchers also looked at various organs growing in the fetuses and saw no signs of damage to anything. Stating:

We did not find any pups with abnormal behaviour.

They found that the peptide was safe for the mice and the baby mice, even at a dose that was 11 times higher than what was needed to provide protection based on the cell assays.

Does The Peptide Help Protect The Mice?

Figure 7

Yes. Here we are looking at some mice that were given a lethal dose of the Zika virus (yes there is such an amount), these mice were either treated with the peptide (Z2, blue) or not (Vehicle, red). You can see that after 10 days all of the untreated mice died, however the mice that received the peptide treatment, upwards of 80% continued to live until the end of the experiment.

• The researchers reported that the amount of virus present in the Z2 peptide treated mice was seven fold lower than in the mice which did not receive the peptide. So it works!

TL;DR/Conclusions

Here the authors reported the generation of a small peptide which is able to stop the Zika virus from being able to infect both cells, and mice (using a mouse model). They showed that the compound does not harm a few cell types in some cell assays, is able to make it to a fetus in the mouse model, and does not cause any harm to the growing fetus (or the mouse in general).

Awesome job Yu et. al. you all may have just created, what with further research could become an amazingly effective treatment for Zika virus infection. Fascinating paper, really great work!

Sources

1. https://www.nature.com/articles/ncomms15672
2. https://www.nature.com/nature/journal/v427/n6972/full/nature02165.html

All Non Cited Images Are From Pixabay.com, Flickr.com, Pexels.com, or Wikipedia.com And Are Available For Reuse Under Creative Commons Licenses

Any Gifs Are From Giphy.com and Are Also Available for Use Under Creative Commons Licences

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