Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins—a human des-octapeptide insulin analog—as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24–PheB25–TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.

人胰岛素及其当前的治疗类似物都显示出自我结合成二聚体和六聚体的倾向，尽管各不相同，这会延迟它们的起效并使糖尿病患者的血糖管理变得困难。最近，我们在锥蜗牛毒液中描述了一种单体的胰岛素样肽，具有中等的人胰岛素样生物活性。在这里，根据结构生物学研究的见解，我们报告了 mini-Ins（一种人去八肽胰岛素类似物）作为结构最小的全效胰岛素的开发。Mini-Ins 是单体，尽管缺乏典型的 B 链 C 端八肽，但与人胰岛素具有相似的受体结合亲和力。四个突变弥补了通常由八肽产生的接触的缺乏。Mini-Ins 还具有与人胰岛素相似的体外胰岛素信号传导和体内生物活性。mini-Ins 的全部生物活性证明了 PheB24-PheB25-TyrB26 芳香三联体的可有可无性，并为治疗性胰岛素的开发开辟了新方向。