Peptides can operate as therapeutic agents that sit within a privileged space between small molecules and larger biologics. Despite examples of their potential to regulate receptors and modulate disease pathways, the development of peptides with drug-like properties remains a challenge. In the quest to optimize physicochemical parameters and improve target selectivity, unnatural amino acids (UAAs) have emerged as critical tools in peptide- and peptidomimetic-based drugs. The utility of UAAs is illustrated by clinically approved drugs such as methyldopa, baclofen, and gabapentin in addition to small drug molecules, for example, bortezomib and sitagliptin. In this Perspective, we outline the strategy and deployment of UAAs in FDA-approved drugs and their targets. We further describe the modulation of the physicochemical properties in peptides using UAAs. Finally, we elucidate how these improved pharmacological parameters and the role played by UAAs impact the progress of analogs in preclinical stages with an emphasis on the role played by UAAs.

中文翻译：

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非天然氨基酸：药物化学和药物发现中的策略、设计和应用


肽可以作为治疗剂发挥作用，位于小分子和大型生物制剂之间的特权空间内。尽管有证据表明它们具有调节受体和调节疾病通路的潜力，但具有药物样特性的肽的开发仍然是一个挑战。在优化物理化学参数和提高靶标选择性的过程中，非天然氨基酸 （UAA） 已成为基于肽和肽模拟物的药物的关键工具。除了硼替佐米和西格列汀等小药分子外，临床批准的药物如甲基多巴、巴氯芬和加巴喷丁也说明了 UAA 的效用。在这个观点中，我们概述了 UAA 在 FDA 批准的药物及其靶点中的策略和部署。我们进一步描述了使用 UAA 对肽中物理化学性质的调节。最后，我们阐明了这些改进的药理参数以及 UAA 所发挥的作用如何影响临床前阶段类似物的进展，重点是 UAA 所发挥的作用。