Geneticists feel cobras on their teeth

Nausea, headache, dizziness, paralysis: millions of people are bitten by venomous snakes every year – with serious consequences: more than 100 000 Bite victims die annually from the poison, according to the World Health Organization (WHO), up to 500 000 further permanent damage such as vision loss or amputation of the limbs. This is mainly due to the fact that antidotes are often not available, but also because the composition of the snake venom is not exactly known.

Now an international team of researchers has discovered the toxins of the South Asian (also “Indian” Cobra ( Well naja ) analyzed in detail based on its genetic makeup. The results could not only enable the development of synthetic antibodies against snake venom, but also that of drugs against various diseases.

Horses as antidote factories

Of the more than 3000 snake species are poisonous about 600, the team led by molecular biologist Somasekar Seshagiri from the California biotechnology company Genentech writes in the journal ” Nature Genetics ”. The vast majority of snake bite deaths are in Asia. In India alone, more than 46. 000 people die each year Snake bites, mainly due to four highly poisonous species: the chain viper ( Daboia russelii ), the common sand-rattle viper ( Echis carinatus ), The common krait ( Bungarus caeruleus ) and the – also called the snake snake – South Asian cobra.

One problem is that antidotes are very expensive and above all in rural areas, where most people are bitten, are hardly available. Such “antivenomes” are currently produced by giving snake venom to horses, for example, and then isolating antibodies from the blood serum of these animals. A second problem is that the exact composition of the poisons, which can vary even within one species, is little known.

To change this, the researchers now decoded the genome of the South Asian cobra, whereby it focused on those genes related to the poison glands. The poison cocktail formed there damages among other things nerve cells, but also other tissues, heart and blood cells. So far, snake venom has been analyzed for proteins using mass spectrometry. With their study, the researchers around Seshagiri are now striving for a new concept. They want to precisely characterize the individual toxins of the species on the basis of their genetic makeup and summarize them in databases. This could be used to produce antidotes synthetically in the future and possibly even produce a broad-spectrum antivenom, they emphasize.

The dose makes the poison

In addition, the findings could lead to new drugs such as painkillers or hypotensive agents. Because a poison that kills nerve cells in high doses can often only numb them in less. And one that attacks the circulatory system may be able to regulate it medically in a different dose. “High-quality venomous snake genomes will enable the creation of a comprehensive catalog of venom-specific toxin genes that can be used to develop synthetic antidotes or certain combinations,” they write.

The researchers came into contact with the venom glands in the cobra genome for 139 genes that code for substances from 33 families of toxins. 96 have correspondences with the king cobra ( Ophiophagus hannah ), the rest 43 Not. 19 Toxins that are produced by the poison glands are therefore at the center of the poison cocktail. Of particular note are the nine three-finger toxins (3FTxs) named after their tripartite form, which act partly on nerves, partly on the heart and partly on other cells and tissues. These 3FTxs are particularly common in the family of poisonous snakes (Elapidae), which include cobras, mambas, sea snakes and the extremely poisonous taipans.

Probably the found 139 Toxin genes responsible for “a wide range of symptoms, including cardiovascular disorders, muscle paralysis, nausea, visual disturbances and systemic effects such as bleeding”.

The neutralization of these main triggers by antibodies could be an effective therapeutic strategy, the authors write. A catalog that contains the toxin variations both within a species and across species is important for the production of a broadly effective antidote. In addition, synthetic humanized antibodies are significantly more effective and much more tolerable than those produced by horses.

“Unheeded health problem”

Guido Westhoff, Chairman of the association Serum-Depot Deutschland, is impressed by the work. “To list the whole poison cocktail, which consists of many toxins, is groundbreaking,” he says. The zoologist is convinced that synthetically produced antidotes would be far more effective and at the same time more tolerable than the current antibodies taken from other mammals. These were sometimes not very targeted and could cause side effects such as allergic reactions.

Martin Metz, dermatologist at the Charité, speaks of a comprehensive analysis that could offer many options. It is “important that someone deals with the topic”. Snake bites are “a huge worldwide health problem that goes unnoticed”. Humanized synthetic antibodies are indeed better and more tolerable than the currently common antivenomes. It remains to be seen whether their manufacture is cheaper, as the authors claim. The toxins database planned by the researchers is also interesting. “If you have a catalog of snake venom and there are many toxins in several species, that would be an option for a broad-spectrum antivenom.” Walter Willems, dpa

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