In
warmer parts of our planet, a snake bite can be traumatic and even fatal without available or
cost-effective medical treatment. According to a recent article in Reuters,
~52,000 people have
died annually from snake bites in India and Bangladesh, and another ~80,000
people havebeen conservatively estimated in TheAmericas and the Carribean. The
highest rate documented
is in sub- Saharan Africa where ~100,000 people have died. This statistic
focuses on snakes
alone and does not includes the insects, frogs, scorpions, lizards, and other
venomous creatures
people have encountered.
According to the Global Snakebite Initiative, ~2.7 million people in India have been bitten. The lack of educational resources and control programs among poor communities continue to bespeak the need to address this as a global health issue.
(Image of an Indian cobra from The Global Snakebite Initiative)
Some of the most venomous creatures reside on land and in water:
(Images from https://sciencebasedlife.wordpress.com/2011/04/12/the-most-poisonousvenomous-animals-in-the-world/)
(Images from http://listverse.com/2007/12/16/top-10-animals-you-didnt-know-were-venomous/)
Despite
the high incidence of these debilitating and often deadly encounters, there are
vastly inadequate
or
unavailable medical resources. Besides the difficulty of obtaining venom
directly from a snake, companies like Sanofi
Pasteur which produces the most effective antivenom in Africa
typically injects
it
into sheep and horses. After allowing time for the animals to develop antibodies, researchers extract enough blood and filter out antibodies to the venom and eventually
create the antivenoms.
The
time and process involved lend to the high cost of treatment – up to $500, an
amount most African
citizens cannot afford. Because
the noted antivenom Fav-Afrique is
not profitable for the company,
Sanofi
Pasteur discontinued manufacturing it last year, and the limited supply of
vials is
expected to run out some time in June 2016.
While
the yin
or dark side of venoms highlights may represent their deadliness,
it also points
to the chemical
challenges vaccine manufacturers face in producing these much needed antidotes. Some man-made or synthesized compounds do not last long enough in the body to
counteract the
venom. In other cases, even venom extracted from the same animal appears differently upon
scientific characterization due to the animal’s age, gender, and the
environment when it
was captured.
(image from http://www.ncbi.nlm.nih.gov/pubmed/12955733)
In the same genus, one can find great variation in venom profiles. These were analyzed by LC/MS (liquid chromatography/mass spectrometry) in the lab of Professor Bryan Fry, aka the Venom Doc, an associate professor at the School of Biological Sciences, University of Queensland.
Then
there is the challenge of identifying the molecules or proteins that target
specific organs in the victim. These tend to be large (sometimes >65,000 Daltons),
compact, and complicated structures tightly
held
in some cases by disulfide bridges.
Chlorotoxin is a polypeptide of 36 amino acids with the red alpha helix and blue beta sheet held together by 4 disulfide bridges highlighted in orange. It comes from the death stalker scorpion.
(image from http://www.mdpi.com/2072-6651/7/4/1079)
(image from http://www.mdpi.com/2072-6651/7/4/1079)
The
yang side of venoms imparts a different aspect of hope and potential that
these compounds
may provide medical therapies for debilitating maladies such as diabetes, high blood
pressure, chronic pain, and muscular dystrophy. Companies and venom experts collaborate
to decipher the complex molecular structures of these peptide molecules and to test
their potential for medical application. A few known examples include:
Captopril
is used to treat hypertension and congestive heart failure. It comes from
the lancehead
viper, Bothrops
insularis.
(Top
image from https://en.wikipedia.org/wiki/Bothrops_insularis;
Left image from https://en.wikipedia.org/wiki/Captopril; Right
image from http://www.euvipharm.com/index.php?/en/product/detail/122/captoril)
Prialt or ziconotide is used to treat chronic pain.
Byetta or exenatide is
used in the treatment of diabetes mellitus type 2. It is based on a hormone in
the saliva of the gila
monster.
Top
left image from http://animals.sandiegozoo.org/animals/gila-monster; top right image
from https://commons.wikimedia.org/wiki/File:Byetta_10_mcg.jpg;Bottom
image from
http://www.polypeptide.com/exenatide-generic-peptides-10.html
Ziconotide is
very soluble in water.
Can you tell why? Look at the
number of amine and oxygen-containing
functional groups.
Also note the S-S bridges
that keep this polypeptide together.
(Top
right image from http://www.popsci.com/scitech/article/2005-11/elan-prialt;top
left image from
http://www.australiangeographic.com.au/news/2014/03/cone-snail-pain-drug-is-non-addictive;
bottom
image from http://www.mdpi.com/1660-3397/13/8/4967/htm)
Currently, venoms continue to bring hope to those who are personally affected by illnesses with no known treatment. One company, Tonus Therapeutics, was co-founded in 2009 by Jeff Harvey from Buffalo, NY. His grandson J. B. was born with a defective gene leading to Duchenne muscular dystrophy. Without any effective options, Jeff searched online and contacted Frederick Sachs, a professor of physiology and biophysics at SUNY-Buffalo.
Jeff Harvey, co-founder of Tonus Therapeutics
Why Professor Sachs? He had discovered and had been researching the effect of venoms on mechanosensitive channels. The latter are membrane proteins that respond to mechanical stress and can a significant impact on ion channels in the cell membrane.
(image from https://www.youtube.com/watch?v=__B5isN07AQ)
Here is a nice video description of how mechanosensitive channels work. Note that alpha helices are part of the secondary structure of a protein and play an active role in controlling the channel's size.
Dr. Sach's research involves a venom peptide known as GsMTx4, and it comes from the Chilean rose tarantula. Dr. Sachs and his research team believe this peptide can close the mechanosensitive ion channel that inhibits the flow of Ca ions which can lead to the breakdown of muscle cells.
Chilean rose tarantula, adult male
(image by Viki, http://creativecommons.org/licenses/by-sa/3.0/, via Wikimedia Commons)
(image from http://www.buffalo.edu/home/feature_story/good-venom.html)
Frederick Sachs,
a professor of physiology and biophysics, - See more at:
http://www.buffalo.edu/home/feature_story/good-venom.html#sthash.ljyGanMq.dpuf
Frederick Sachs,
a professor of physiology and biophysics, - See more at:
http://www.buffalo.edu/home/feature_story/good-venom.html#sthash.ljyGanMq.dpuf
