Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol–water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.

中文翻译：

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口服吸收环肽

肽和蛋白质在哺乳动物中不是口服生物可利用的，尽管一些肽在肠内少量吸收。多肽通常太大且极性很大，无法通过脂质膜被动扩散，而大多数已知的主动转运机制仅能促进细胞吸收非常小的肽。需要对分子量大于500 Da的肽进行系统评估，以鉴定影响口服生物利用度的参数。在这里，我们描述了125个环肽，其中包含4到37个氨基酸，它们被哺乳动物口服吸收。环化通过去除可裂解的N和C末端以及从代谢酶中屏蔽组分，从而最大程度地减少了肠道，血​​液和组织的降解。环化还将肽折叠成具有生物活性的构象，该构象决定了极性原子被水和脂质溶剂化的程度，因此会影响口服生物利用度。分析了影响口服吸收和生物利用度的关键化学性质，包括分子量，辛醇-水分配，氢键供体/受体，可旋转键和极性表面积。尽管通常较少的氢键供体和降低的柔韧性通常有利于口服吸收，但是环状肽在不同程度上违反了传统上认为对药物样小分子的口服生物利用度重要的所有限制。辛醇-水分配，氢键供体/受体，可旋转键和极性表面积。尽管通常较少的氢键供体和降低的柔韧性通常有利于口服吸收，但是环状肽在不同程度上违反了传统上认为对药物样小分子的口服生物利用度重要的所有限制。辛醇-水分配，氢键供体/受体，可旋转键和极性表面积。尽管通常较少的氢键供体和降低的柔韧性通常有利于口服吸收，但是环状肽在不同程度上违反了传统上认为对药物样小分子的口服生物利用度重要的所有限制。