A Sea Snail Toxin Could Inspire New Diabetes Drugs

Though small, cone snails are formidable hunters, producing a variety of toxins—many of which are valuable for drug research—to immobilize prey and deter predators. In 2015, researchers discovered that some species, like Conus geographus, make venoms that contain con-insulin, a toxin that mimics fish insulin and induces hypoglycemic shock in nearby prey.¹ 

These findings inspired Ho Yan Yeung, a postdoctoral researcher in Helena Safavi-Hemamiâ€s group at the University of Utah, to investigate whether cone snails produced other toxins that mimic fish hormones. While con-insulin quickly lowered blood sugar, Yeung hypothesized that another cone snail version of a glucose-regulating hormone was needed to maintain a longer-lasting effect: keeping blood sugar low to prevent the fish from escaping. One hormone that could serve this function is somatostatin, which acts as a brake to prevent blood sugar from rising to normal levels.

To find these snail-produced hormone mimics, Safaviâ€s team sequenced RNA from the C. geographus venom gland and used mass spectroscopy to identify two somatostatin-like toxins (Consomatins G1 and G2).² X-ray crystallography of Consomatin G1 revealed that its structure closely resembled a therapeutic somatostatin analog, prompting further exploration. There are five types of somatostatin receptors (SSTR); human somatostatin binds to all five, while the snail version binds to only one. This research, published in Nature Communications, revealed that C. geographus produced a weaponized somatostatin that exhibits more specific binding to somatostatin receptors than human analogs.³ This discovery could lead to improved targeting for drugs for diabetes.

Blood glucose levels are mainly regulated by the opposing actions of insulin and glucagon—insulin lowers blood sugar levels, while glucagon raises it. Glucagon is regulated by the inhibitory effects of somatostatin. Human somatostatin binds to all five SSTRs, while the drug analog octreotide only binds to SSTR₂. However, the researchers hypothesized that the cone snailâ€s version of somatostatin, Consomatin G1, might also selectively target the hormone-regulating receptor SSTR₂ due to its structural similarity to octreotide. This could help researchers design more specific drugs that regulate glucose homeostasis and treat somatostatin signaling-related disorders, such as excess growth hormones in acromegaly and neuroendocrine tumors.

First, the researchers assessed how well Consomatin G1 bound to all five SSTR receptors, by synthesizing the previously identified peptide (Consomatin pG1). This peptide, isolated from cone snail venom, has similar amino acid sequences to somatostatin. The researchers found that Consomatin pG1 could selectively activate SSTR₂ in human cells. SSTR₂ is a highly expressed receptor in human and rodent pancreatic alpha cells thought to block glucagon release.

Next, Yeung wanted to determine how this toxin affected glucagon secretion in rodent tissue. She conducted experiments on tissues, such as the rat pancreas and mouse pancreatic islets. Her experiments revealed that Consomatin pG1 was quite potent and targeted somatostatin by suppressing glucagon secretion. 

Consomatin pG1 interacted with SSTR₂ in Yeungâ€s mammalian cell and tissue experiments, but Yeung now wanted to see the effects of the toxin on fish SSTR₂ receptors. Zebrafish express two subtypes of SSTR₂ receptors which are homologous to the single type of SSTR₂ receptor in humans.⁴ The researchers tested Consomatin pG1 activity against both fish receptors. Human somatostatin served as a control and activated both SSTR₂ receptors. However, Yeung was surprised that Consomatin pG1 only activated one of the two receptor forms, while crude C. geographus venom activated both. This suggests that the native Consomatin G1 toxin had a different chemical identity than the synthesized peptide.

To determine how the peptide and the complete toxin differed, the researchers isolated the native peptide (Consomatin nG1) from C. geographus venom. Then, they screened for peptide sequences with high activation of the SSTR₂ receptor. “It turns out that itâ€s a super massive toxin compared to the predicted form, and that it is also heavily chemically modified, which is something that we hadnâ€t really expected at all,†said Yeung.

When Yeung compared the predicted toxin with the native toxin, she observed an unusual structure. The native toxin had a heavily modified region of glycosylated proteins that closely mimicked a previously identified glycosylated somatostatin from fish pancreas which is crucial for activating the fish SSTR₂ receptors.⁵ These findings demonstrate the cone snailâ€s ability to produce somatostatins that closely mimic pancreatic hormones in fish prey.

“This is probably the first example of a pure kind of mammalian hormone to regulate the prey-hunting process,†said Danny Chou, a biochemist at Stanford University who was not involved in the study. Consomatin G1â€s protein structure provides researchers with insights into natural compounds with chemical mimicry. Chou remarked that this work with venom somatostatin, branching off Safavi-Hemamiâ€s previous venom insulin work, could help researchers design potential therapeutics. For instance, some neuroendocrine tumors predominantly express one receptor type, such as SSTR₂, while others express multiple subtypes of SSTR receptors. The cone snailâ€s version of somatostatin, which closely resembles existing synthetic drug analogs, and its natural specificity is a promising area for further exploration.

Yeung noted that these cone snails are a “treasure trove,” and added, “Nature really offers us a lot of different kinds of resources for drug development that we should keep on looking into with all these amazing venomous animals.†She believes that many more toxins might contribute to this glucose-regulating hunting strategy and continues to dissect the cone snailâ€s deadly venom for clinical applications.