Small and fast

The venom of cone snails helped create a fast-acting mini-insulin

Sergey Kolenov, N+1

Based on data on the venom of predatory cone snails, scientists have developed a miniature version of insulin that acts several times faster than human. This effect is achieved due to the fact that mini-insulin is not able to form complexes of several molecules. As the researchers note in their article for Nature Structural and Molecular Biology (Xiong et al., A structurally minimized yet fully active insulin based on cone-snail venom insulin principles), the compound can form the basis of new drugs to reduce blood glucose levels. 

Human insulin and its analogues are widely used in the treatment of diabetes mellitus. However, these substances have a serious drawback – the tendency to form complexes of two or six molecules. After injection under the skin, they break up into monomers only after 15-30 minutes, which slows down the effect of the injection. 

In search of analogues that can quickly reduce the level of glucose in the blood, experts turned to an unusual source – predatory sea snails from the family of cones (Conidae). These mollusks hunt fish and invertebrates with venom injected through modified radula teeth. 

The venom of cones is a complex chemical cocktail, the composition of which varies from species to species. For example, in the geographical cone (Conus geographus), it includes fast-acting insulin variants that cause a sharp drop in blood sugar levels and hypoglycemic shock in the victim.

Researchers led by Danny Hung-Chieh Chou from the University of Utah have carefully studied the insulin from the venom of cones. A few years ago, the team members proved that one of their molecules, Con-Ins-G1, is able to bind to the human insulin receptor. This version of insulin is shorter than human and does not form dimers and geskamirs, which allows it to act much faster. Unfortunately, this compound acts on human receptors 20-30 times weaker than normal insulin.

At a new stage, scientists decided to combine the best qualities of Con-Ins-G1 and human insulin in one molecule. To do this, they reconstructed the structure of the insulin cone and its interaction with the receptor using crystallography and cryo-electron microscopy. 

It turned out that the inability of Con-Ins-G1 to form dimers and hexamers is associated with the absence of a residue at the C-end of the B-chain. In human insulin, an octapeptide is located on it, which is critically important for interaction with the receptor. However, in cones, its deficiency is compensated by the amino acid residues TyrB20 and TyrB15, the first of which is more important.

Using the data obtained, the authors developed a small hybrid molecule called mini-insulin. Like Con-Ins-G1, it has an amino acid residue of TyrB20 and a strongly shortened B-chain. In addition, mini-insulin carries amino acid residues HisA8, GluB10 and ArgA9, which enhance interaction with the receptor. 

Experiments in vitro and with laboratory mice have shown that this molecule binds to the insulin receptor as effectively as human insulin. At the same time, it does not form complexes, which allows it to act almost instantly. As the authors note, mini-insulin is the shortest molecule of its kind with the functions of insulin.

The modest size not only provides mini-insulin with speed, but also facilitates its synthesis. This makes it the main candidate for the role of a new generation drug for regulating blood glucose levels.

Portal "Eternal youth" http://vechnayamolodost.ru