Based on the venom of predatory snails-cones, scientists have developed a miniature version of insulin, which operates several times faster than human. This effect is achieved by the fact that the mini-insulin is not able to form complexes of several molecules. As noted by the researchers in an article for Nature Structural and Molecular Biology, the connection may be the basis of new drugs to reduce the level of glucose in the blood.
Human insulin and its analogues are widely used in the treatment of diabetes. However, these substances have a serious flaw – a tendency to form complexes with two or six molecules. After the introduction under the skin, they break down into monomers only after 15-30 minutes, which slows down the effect of the injection.
In search of analogs to quickly reduce the level of glucose in the blood, experts have turned to an unusual source – the predatory marine snails of the family of cones (Conidae). These mollusks prey on fish and invertebrates by means of poison, which is injected through modified teeth radula. The venom of the cones is a complex chemical cocktail, the composition of which varies from species to species. For example, the geographic cone (Conus geographus) it includes a fast-acting versions of insulin, causing the victim to sharp drop in blood sugar and hypoglycemic shock.
The researchers, headed by Danny Hoon Chieh Chou (Danny Hung-Chieh Chou) from the University of Utah examined the insulin from the venom of the cones. A few years ago, members of the team proved that one of them molecules, Con-Ins G1, able to bind to the insulin receptor of the person. This variant of human insulin is shorter and does not form dimers and hiscamera that allows it to act much faster. Unfortunately, the receptors of humans, this connection operates 20-30 times weaker than that of regular insulin.
In the new phase, the researchers decided to combine in one molecule the best quality Con-Ins G1 and human insulin. To do this, they reconstructed the structure of insulin of a cone and its interaction with the receptor by the methods of crystallography and cryoelectron microscopy.
It turned out that the inability of Con-Ins G1 to form dimers and hexamers linked to lack of residue to the C-Terminus of the B-chain. In the human insulin it is the octapeptide that is critical for interaction with the receptor. However, the cones lack kompensiruet due to the amino acid residues TyrB20 and TyrB15, the first of which is more important.
Using the obtained data, the authors have developed a hybrid molecule, called a mini-insulin. Like Con-Ins G1, it has the amino acid residue TyrB20 and greatly shortened B-chain. In addition, mini insulin carries the amino acid residues HisA8, GluB10 and ArgA9 that enhance the interaction with the receptor.
In vitro experiments and involving laboratory mice showed that the molecule binds to the insulin receptor as effectively as human insulin. While it is not formed complexes, which allows it to operate almost instantly. As the authors note, the mini-insulin is the shortest of its kind molecule that performs the functions of insulin.
Small size not only provide a mini-insulin performance, but also facilitate synthesis. This makes it a Prime candidate for the role of new generation product to regulate the level of glucose in the blood.
Recently, researchers have developed a set of insulin and a cationic polymer which is capable of releasing the right amount of this hormone depending on the current level of glucose in the blood. As have shown experiments on mice and pigs with diabetes, a single injection of this suspension ensures normal level of glucose in the blood much longer than regular insulin