Scientists already know that the venom of 锥形蜗牛, which prowl the ocean floor for a fish dinner, contains compounds that can be adapted as pharmaceuticals to treat chronic pain, 糖尿病和其他人类疾病. But the 锥形蜗牛’ venom has more secrets yet to be revealed. 一项新的研究发表在 科学的进步, 研究人员报告说，一组锥体蜗牛产生一种类似于激素生长抑素的毒液化合物.
当他们继续了解更多关于这种毒液化合物及其可能的药物应用时, the results show the wide variety of drug leads that venomous animals produce, designed and refined over millions of years.
"We have to broaden the scope of what we expect that these venomous animals make, assuming that they could really be making anything,Helena Safavi-Hemami说, 犹他大学的兼职助理教授和哥本哈根大学的副教授. "We should look very broadly and keep an open eye for completely new compounds."
"Cone 蜗牛 venom is like a natural library of compounds," adds Iris Bea Ramiro of the University of Copenhagen. "It is just a matter of finding what is in that library."
找到完整的研究 在大发娱乐. 这项研究是由美国农业部资助的.S. 国防部, 一个小镇青年调查员格兰特, 科学和技术部——菲律宾卫生研究与发展理事会, 美国国际开发署和本宁协会.
从薄荷岛开始
The story begins in the Philippines, on the island of Bohol w在大发娱乐 Ramiro grew up. 尽管她和大多数波霍拉诺人除了在海滩上发现贝壳外，并不经常遇到锥蜗牛, fishermen knew how to find and catch the venomous 蜗牛s, which are often sold to shell collectors and are sometimes eaten. 一位渔民告诉拉米罗，他的父母警告他不要吃蜗牛体内的豆状器官.
这种豆状结构实际上是一个与分泌毒液的腺体相连的球茎,拉米罗说.
有些锥螺是捕鱼者. Some of those use a "taser-and-tether" hunting strategy, 把有刺的鱼钩射进鱼里，释放出一股毒液，用化学方法使鱼触电并瘫痪. 另一些则使用网捕策略, 向水中释放一团含有化合物的毒液，使鱼失去感官和方向感.
Of the estimated eight groups of fish hunting 锥形蜗牛, 虽然, only half have been extensively studied. Among the least-studied lineages are the Asprella 锥形蜗牛. They’re not shallow-water 蜗牛s, like some others. 它们喜欢深水, at depths of 200-800 feet (60-250 m), and have been less accessible to scientists.
As a graduate student at the University of the Philippines, Ramiro began studying 圆锥rolani，一种 Asprella 蜗牛. "No one in our lab was working on it at that time," she says. “我只是想从蛇的毒液中找出任何小的肽（氨基酸链） C. rolani that had unusual or interesting activity in mice."
她找到了一个. A small peptide from the venom caused mice to act sluggishly or unresponsive. 但这是缓慢的, 几乎没有预期的效果，因为其他锥螺产生的毒液几乎立即起作用. 它与激素生长抑素有一些相似之处（稍后会详细介绍），但还不足以结论性地说毒液肽和人类激素在功能上是相关的.
While exploring how and why the venom worked, Ramiro made a visit to the University of Utah, 一个锥体蜗牛研究中心.
We can spend a lot of time trying to design good hormone drugs, or we could try to look at nature more often.
锥形蜗牛在美国
Far from the glittering waters of the Pacific, U researchers have been studying 锥形蜗牛 and their venom since 1970, when Baldomero "Toto" Olivera arrived in Salt Lake City, bringing the cone 蜗牛 research he’d begun in his native Philippines.
几十年的研究已经大发娱乐提供了大量关于毒液化合物如何与猎物身体相互作用的信息, 包括毒液如何与体内的受体相互作用，并压倒自然的生化过程. 奥利维拉和他的同事们调查了这些效应是否可以作为药物用于人类. One effort yielded a pain medication, Prialt. 另一个, in which Safavi played a leading role at the U as an assistant professor, 研究了锥体蜗牛产生的胰岛素类似物如何被适应为糖尿病患者的速效胰岛素.
“不知怎么的，锥体蜗牛吸收了它们的一些激素，把它们变成了武器，”萨法维说. So she and other researchers helped Ramiro compare the peptide she’d found, 现在称为Consomatin Ro1, 已知的人类蛋白质.
弗兰克·惠特比, a research associate professor in the Department of Biochemistry, used X-ray crystallography to determine the structure of Consomatin Ro1. “这是一个重要的贡献，因为它表明somatin Ro1不像生长抑素，而是像生长抑素的药物类似物奥曲肽,克里斯托弗·希尔说, distinguished professor of biochemistry.
Meanwhile the research team also worked with local fishermen off Cebu, 薄荷岛附近的一个岛屿, 带 Asprella 把标本送到实验室观察它们的行为，并进一步了解它们的生物化学.
拉米罗说，她花了一年的时间来确认她最初从细菌中分离出来的肽 C. rolani 她说，蜗牛“以独特的选择性”激活了人类生长抑素五种受体中的两种.
“那,萨法维说, “大发娱乐真的很想了解它的作用，以及它如何比生长抑素更好."
蜗牛和蛇
生长抑素是一种激素, in humans and many other vertebrates, is generally an inhibitor—kind of a wet blanket. It’s the main inhibitor of growth hormone, and can be used to treat the excessive growth disorder acromegaly. It also inhibits hormones in the pancreas and signals of pain and inflammation.
“所以这种激素有很多, many different functions in the human body,萨法维说, “但它总是阻挡一些东西. 正因为如此，一段时间以来，它一直是一种有趣的药物开发激素."
像生长抑素这样的激素是如何作为武器化的毒液起作用的，尤其是当它作用缓慢的时候? 最好的理解方式是, 研究人员说, is to look to another predator with a slow-acting venom: the rattlesnake.
响尾蛇, 毒蛇和眼镜蛇已经发展出一种狩猎策略来保护自己免受可能反击的危险猎物的伤害. The snakes strike, injecting their venom, and then retreat. 然后，它们等待并跟踪猎物，直到毒液完全发挥作用，猎物已经死亡或接近死亡，可以安全接近和食用.
对水箱中锥蜗牛的观察表明，它们与响尾蛇的捕食策略相似. 注射毒液后, 蜗牛会等待, 有时长达三个小时, before delivering a second injection and waiting again.
"And only when the prey is really incapacitated and unable to swim, 他们来吃它,萨法维说. "If you don’t catch the prey immediately, you have the advantage of just waiting until the prey can no longer move. That’s particularly important if the prey can fight back."
How does a venom component that mimics somatostatin help with that strategy? 现在还不清楚. 研究表明，促生长素Ro1可以阻断小鼠的疼痛，其效果与吗啡相似, and it may be used to block pain so that prey doesn’t know it’s been struck, 影响说. Different species of fish hunters may use these toxins for different purposes.
微型药物设计者
作为生长抑素类似物, 影响说, Consomatin Ro1 is structured "as if it was designed by drug makers." The molecule is short, stable and efficient in the receptors it targets.
That’s likely a reflection of the process of evolution. Cone 蜗牛s likely began using their own somatostatin in venom and then, through generations of trial and error, refined the compound for maximum effectiveness. 这对大发娱乐来说是一个优势, 因为鱼和人类的生物学非常相似，所以对鱼有效的化合物可能对人类也有效.
Consomatin Ro1是否比市场上已有的用于治疗生长障碍或肿瘤的生长抑素类似药物更有效还有待观察.
萨法维说：“锥形蜗牛的优势在于种类繁多。. "And we know that many of these species make somatostatin, so the chances of finding the best analog might be pretty high."
未来的发展方向
下一个, the research team wants to investigate the origin of Consomatin Ro1 in 蜗牛s, 以及更好地了解这种化合物作为消炎或止痛药的潜力. 他们还将研究对这种化合物的修改是否会使其更有用.
研究结果显示了有毒动物如何将激素转化为武器，并表明毒液中生化工具的范围可能比之前想象的要广泛.
"T在大发娱乐’s evidence that viruses also turn hormones into weapons,萨法维说. "We can spend a lot of time trying to design good hormone drugs, or we could try to look at nature more often. 我认为如果大发娱乐选择后者, we might be more successful or we might be faster in our drug development efforts.萨法维将于2022年夏天回到美国，担任生物化学副教授，届时她将继续这项工作.
希尔说：“这为下一代疗法的发展大发娱乐提供了洞见。. “更普遍, 这是一个很好的例子，说明自然界的进化已经开发出了类似药物的天然产物，这些天然产物具有改善人类健康的巨大潜力."
“从锥体蜗牛中发现新的多肽是有趣和令人兴奋的，但这可能是一个漫长而艰难的过程,拉米罗说, adding that the integration of various disciplines including biology, biochemistry and pharmacology have made this study successful. “大发娱乐仍然可以从锥蜗牛和它们的毒液中发现、发现和学习很多东西."
找到完整的研究 在大发娱乐.