The medical community frequently utilizes the established practice of synthesizing medications based on chemicals found in nonhuman, living creatures, such as GLP-1 that was discovered in the saliva of Gila monsters that is now commonly used to treat diabetes in humans. Emerging studies indicate that a specialized, insulin-like toxic protein used by cone snails to immobilize prey may be a new weapon in the pharmacotherapeutic arsenal for treatment interventions. In an article published in Proteins: Structure, Function, and Bioinformatics, researchers from the University of New Hampshire report their findings and hopes for a future of new possibilities using this venom for treating humans with diabetes.

Lead author Biswajit Gorai, a postdoctoral research associate at the University of New Hampshire, Durham, and colleagues embarked on an effort to model the subtypes found in the toxin and explore how these chemicals interact with target sites, including comparing the binding site energy, to design an active insulin analog with "superior pharmacologic potential." Conus geographus (cone snail insulins [Con-Ins-G1]) releases this toxin, which induces hypoglycemic shock when they sting, immobilizing fish.  

C geographus is a specialized predator of fish, which it swallows whole after paralyzing its prey with venom. This species is also dangerous to humans, reportedly causing fatalities, with children succumbing more frequently to the stings. Funding for this research was awarded by the National Institute of General Medical Sciences of the National Institutes of Health.

Because the peptide sequence of the snail venom was observed to be shorter than that of humans and the length of the peptide correlates to the ability of the insulin to bind to receptors, the team hypothesized that modifications might translate into a more successful outcome. Therefore, the team explored modified sequences for six different Con-Ins analogs modeled from the C geographus template. The newly created variants were made up of much shorter peptide chains than human insulin, missing the last eight residues of the B-chain. Using multiple computerized simulations to study the interaction with each Con-Ins variant complex with the human insulin receptor, the team observed that each insulin complex was strongly bound, remained stable, and appeared to be a realistic potential human insulin substitute.
"Diabetes is rising at an alarming rate, and it's become increasingly important to find new alternatives for developing effective and budget-friendly drugs for patients suffering with the disease," said Harish Vashisth, associate professor of chemical engineering and corresponding author, adding, "Our work found that the modeled Con-Ins variants, or analogs, bind even better to receptors in the body than the human hormone and may work faster which could make them a favorable option for stabilizing blood sugar levels and a potential for new therapeutics."

Acknowledging the limitations of their study, the researchers also provided insight into the future value of their work. "While more studies are needed, our research shows that despite the shorter peptide sequences, the cone snail venom could be a viable substitute and we are hopeful it will motivate future designs for new fast-acting drug options," said Dr. Gorai.
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