Vorherr Thomas, Lewis Ian, Berghausen Joerg, Desrayaud Sandrine, Schaefer Michael
Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
Int J Pept Res Ther. 2018;24(1):35-48. doi: 10.1007/s10989-017-9590-8. Epub 2017 Mar 28.
Recently, a variety of studies concerned with the permeability and oral bioavailability of cyclic peptides have been reported. In particular, strategies aiming at modifying peptides to maintain or to enhance solubility while enabling permeability constitute a significant challenge, but are of high interest to ensure a smooth drug discovery process. Current methodologies include -methylation, matching of hydrogen bonding acceptors and donors across the macrocycle, and additional masking of polarity. In this study, we investigate further the pivotal effects of shielding on permeability and studied the metabolism of the corresponding peptides in more detail by comparing peptide concentrations in the portal versus the jugular vein in rats. Interestingly, minor changes in one particular side chain impacts both permeability and liver metabolism.
最近，已经报道了各种关于环肽通透性和口服生物利用度的研究。特别是，旨在修饰肽以保持或提高溶解度同时实现通透性的策略构成了一项重大挑战，但对于确保药物发现过程的顺利进行具有很高的研究价值。目前的方法包括α-甲基化、大环上氢键受体和供体的匹配以及极性的额外掩盖。在本研究中，我们进一步研究了屏蔽对通透性的关键影响，并通过比较大鼠门静脉和颈静脉中的肽浓度，更详细地研究了相应肽的代谢。有趣的是，一个特定侧链的微小变化会影响通透性和肝脏代谢。
