Bio-inspired 胰岛素 may act three times faster than current products
(SALT LAKE CITY) - University of Utah researchers have found that the structure of an 胰岛素 molecule produced by predatory cone snails may be an improvement over current fast-acting therapeutic 胰岛素. The finding suggests that the cone snail 胰岛素, produced by the snails to stun their prey, could begin working in as few as five minutes, compared with 15 minutes for the fastest-acting 胰岛素 currently available. 生物学家 海伦娜影响, co-author on a paper describing the cone snail 胰岛素 published September 12 in 自然结构 & 分子生物学, says that studying complex venom cocktails can open doors to new drug discoveries.
"You look at what venoms animals make to affect the physiology of their prey, and you use that as a starting point,她说. "You can get new ideas from venoms. To have something that has already been evolved — that's a huge advantage."
Along with colleagues from Australia, U biochemists 丹尼周 and Maria Disotuar, and biologists Joanna Gajewiak and Baldomero奥利维拉 对研究有贡献.
小而快
Human 胰岛素 is a hormone that is produced in the pancreas and secreted to aid in the body's uptake of glucose. The 胰岛素 molecule consists of an "A" region and a "B" region. Diabetes mellitus disorders arise from impairment of the body's normal production of 胰岛素. The most effective treatment for 糖尿病 is injection of synthetic 胰岛素.
But a part of the B region causes 胰岛素 molecules to stick together and form aggregations of six 胰岛素 molecules. It's how 胰岛素 is stored in the pancreas. But injected 胰岛素 must de-aggregate into individual molecules before doing a person any good – and that process can take up to an hour. The fastest-acting 胰岛素 on the market, Humalog, still takes 15-30 minutes to become active. "The ideal scenario would be to take the region off of the B chain萨法维说. "But then you completely abolish 胰岛素 activity."
周, 影响, and colleagues found that 胰岛素 produced by the cone snail 圆锥geographus lacked the segment of the B region that causes aggregation. Tests on 胰岛素 receptors in the lab showed that although the snail 胰岛素 was less effective than human 胰岛素, 它仍然有效, and could possibly start acting in five minutes.
胰岛素作为武器
The 圆锥geographus snail is a predatory cone snail, eating fish. C. geographus and its relatives have developed complex brews of venoms to rapidly paralyze prey fish. Some snails use venom to overload the fish's nervous system, sending it into "excitotoxic shock.其他的，包括C. geographus, 分泌胰岛素, 和其他化合物一起, 下水, causing the blood sugar in nearby fish to plummet and sending the fish into hypoglycemic sedation. Once the fish is stunned, the snail engulfs and consumes it.
In 2015, 影响 and U biology professor Baldomero奥利维拉 described C. geographus' so-called "weaponized 胰岛素," suited for quick action. 在8月8日发表的一篇相关论文中. 16 in 分子生物学 and Evolution, 影响 and colleagues describe how weaponized 胰岛素s evolved rapidly to more effectively target prey.
It makes sense because the snail has to very rapidly induce 胰岛素 shock in its fish prey, so it has evolved something very fast acting,萨法维说.
让蜗牛胰岛素发挥作用
Studying the structure of the cone snail 胰岛素 could help researchers modify human 胰岛素 to lose its self-aggregation but retain its potency, 影响说. "Now we can look at the human 胰岛素 and see if we can make it more snail-like."
The team still needs to conduct more experiments to measure how quickly snail 胰岛素, 或者改良的人类胰岛素, would work when injected into an organism. Fish are affected almost instantly because the 胰岛素 passes over the gills. In humans, the process may take a few minutes longer.
周 studies human 胰岛素 for use in an artificial pancreas device that could automatically deliver 胰岛素 in response to changing blood sugar levels, 就像自然器官一样. The first generation of such a device may be available as soon as next year. 锥形蜗牛胰岛素, although "still not as good as we want for human use,周说, could replace the current fast-acting 胰岛素 used in artificial pancreas development.
Bio-inspiration
"It's really about learning from nature,周说. 影响同意. "People think it's easy to make drugs,她说. “但你从哪里开始呢？? You have to have some kind of idea of what a drug should look like, what kind of properties the drug should have, so it's very difficult to design novel drugs. That's why we use the snail venom system."
Funding for the study was provided by the National Health and Medical 研究 Council of Australia, the National Institutes of Health, USTAR和欧盟委员会.
Comparison of the structures of 胰岛素 in 圆锥geographus (red/white) and in humans (blue/white and green). The green B-chain terminal segment is absent in the C. geographus 胰岛素.
图片由迈克·劳伦斯大发娱乐提供