Healing compounds in scorpion venom

A scorpion native to eastern Mexico may have more than just toxin in its sting. Researchers from Stanford University and Mexico have discovered that venom also contains two compounds that change color could help fight bacterial infections.

The team not only isolated the compounds contained in the venom of the scorpion, but also synthesized them in the laboratory and verified that the laboratory-made versions killed staphylococcal and tuberculosis bacteria resistant to drugs in tissue samples and mice.

The results, published June 10 in the journal Proceedings of the National Academy of Sciences, highlight the potential pharmacological treasures to discover in the toxins of scorpions, snakes, snails and other poisonous creatures.

"In volume, the scorpion venom is one of the most valuable materials in the world. It would cost $ 39 million to produce a gallon, "said lead author of the study, Richard Zare, who led the Stanford group. "If you only depended on scorpions to produce it, no one would have the means to pay for it, so it's important to determine what the essential ingredients are and to be able to synthesize them."

Treats scorpions

Zare worked with his colleagues in Mexico, including Lourival Possani, professor of molecular medicine at the National University of Mexico, whose students took specimens of the scorpion. Diplocentrus melici to study.

"The collection of this species of scorpion is difficult because during the winter and the dry season, the scorpion is buried," said Possani. "We can only find it during the rainy season."

Possani has focused for 45 years on the identification of compounds with pharmacological potential in scorpion venom. His group has already discovered potent antibiotics, insecticides and antimalarials hidden in the poison of the arachnid.

When Mexican researchers are treating the venom of D. melici – a process that involves stimulating the tail with slight electrical impulses – they noticed that the venom changed color, from light to brownish, when it was exposed to the air.

When Possani and his lab investigated this unusual color change, they discovered two chemical compounds they thought were responsible. One of the compounds became red when it was exposed to the air, while the other became blue.

To learn more about each compound, Possani contacted Zare's group at Stanford, known for identifying and synthesizing chemicals.

Stanford postdoctoral researchers Shibdas Banerjee and Gnanamani Elumalai were able to determine the molecular structure of the two compounds with the help of a tiny sample of the venom. "We only had 0.5 microliters of venom," said Zare, Margaret Blake Wilbur Professor of Natural Science at the Stanford School of Humanities. "It's ten times less than the amount of blood that a mosquito will suck in one portion."

Using clues drawn from the use of different chemical analysis techniques, Stanford scientists concluded that the ingredients that change color in the venom were two benzoquinones until then unknown – a class of ring-shaped molecules known for its antimicrobial properties.

The benzoquinones of the scorpion venom seemed to be almost identical to each other. "The two compounds are structurally related, but while red has an oxygen atom on one of its branches, blue has a sulfur atom," Banerjee said.

The group confirmed the structures of the compounds when, through many trials and errors, they learned to synthesize them. "Many of the reactions you write on paper that seem to work do not work when you test them in the lab. So you have to be patient and have many different ideas, "said Shyam Sathyamoorthi, a Ph.D. student at Stanford. led the synthesis efforts.

Drug potential

Zare's laboratory sent a batch of newly synthesized benzoquinones to Rogelio Hernández-Pando, pathologist at the Salvador Zubirán National Institute of Health Sciences and Nutrition in Mexico City, whose group tested the activity biological compounds made in the laboratory.

The Hernández-Pando group found that red benzoquinone was particularly effective at killing highly infectious bacteria, staphylococcus, while blue was deadly for both normal and multidrug-resistant bacteria responsible for tuberculosis.

"We discovered that these compounds kill the bacteria, but then the question became:" Will that kill you too? "" Zare said. "And the answer is no: the Hernández-Pando group has shown that the blue compound kills the bacterium of tuberculosis but leaves intact the lining of the lungs of the mice."

Possani said that the antimicrobial properties of the compounds may not have been discovered if the Zare group had not found a way to synthesize them, which would allow them to be produced in larger quantities. "The amount of venom components we can get from animals is extremely small," said Possani. "The synthesis of the compounds was decisive for the success of this work."

Mexican and Stanford scientists are considering new collaborations to determine if compounds isolated from venom can be turned into drugs and why they are present in venom in the first place.

"These compounds might not be the toxic component of venom," said Zare. "We have no idea why the scorpion makes these compounds. There are more mysteries.

Zare is also a member of Stanford Bio-X, the Wu Tsai Neuroscience Institute and the Stanford Woods Institute for the Environment, and a faculty member at Stanford ChEM-H. Other authors come from the National University of Mexico in Cuernava and the National Institute of Health Sciences and Nutrition Salvador Zubirán in Mexico City.

Stanford's work was funded by the Air Force's Bureau of Scientific Research.

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