Department of Clinical Pharmacology , Dalian Medical University , Dalian 116044 , China.
Key Laboratory of Structure-Based Drug Design and Discovery , Shenyang Pharmaceutical University, Ministry of Education , Shenyang 110016 , China.
J Med Chem. 2019 Sep 12;62(17):7708-7721. doi: 10.1021/acs.jmedchem.9b00358. Epub 2019 Sep 3.
The cyclic dipeptides generally present lower affinity toward intestinal oligopeptide transporter 1 (PEPT1) than the linear dipeptides. JBP485 (cyclo(l-Hyp-l-Ser)) is a low-affinity substrate of PEPT1 with poor oral bioavailability. However, JBP923 (l-Hyp-l-Ser) is a high-affinity substrate of PEPT1 with high oral absorption. We hypothesize that the bioactivatable pseudo-tripeptidization prodrug strategy is promising to increase the affinity of cyclic dipeptides toward PEPT1. To test our hypothesis, we design five amino acid ester prodrugs of JBP485. Compared with JBP485, the optimal prodrug (JBP485-3-CH--valine, J3V) demonstrates improved affinity of PEPT1, oral bioavailability in rats and beagle dogs. Moreover, J3V can dose-dependently protect against liver injury. Additionally, J3V is stable in the gastrointestinal tract, beneficial to the PEPT1-mediated membrane transport, and is bioactivated in the enterocytes and hepatic cells, essential to elicit its bioactivity. In summary, the bioactivatable pseudo-tripeptidization strategy shows potential in increasing affinity of PEPT1 to enhance oral bioavailability of cyclic dipeptides.
环状二肽通常比线性二肽对肠道寡肽转运蛋白 1（PEPT1）的亲和力更低。JBP485（环（l-羟脯氨酸-l-丝氨酸））是 PEPT1 的低亲和力底物，口服生物利用度差。然而，JBP923（l-羟脯氨酸-l-丝氨酸）是 PEPT1 的高亲和力底物，具有较高的口服吸收率。我们假设生物可激活的假三肽化前药策略有望提高环状二肽对 PEPT1 的亲和力。为了验证我们的假设，我们设计了 JBP485 的五个氨基酸酯前药。与 JBP485 相比，最佳前药（JBP485-3-CH--缬氨酸，J3V）显示出对 PEPT1 的亲和力提高、大鼠和比格犬的口服生物利用度提高以及对肝损伤的保护作用。此外，J3V 可以剂量依赖性地保护肝脏免受损伤。此外，J3V 在胃肠道中稳定，有利于 PEPT1 介导的膜转运，并且在肠细胞和肝细胞中被生物激活，这对于发挥其生物活性至关重要。综上所述，生物可激活的假三肽化策略有望提高 PEPT1 对环状二肽的亲和力，从而提高其口服生物利用度。
