Bioactivatable Pseudotripeptidization of Cyclic Dipeptides To Increase the Affinity toward Oligopeptide Transporter 1 for Enhanced Oral Absorption: An Application to Cyclo(L‑Hyp‑L‑Ser) (JBP485)
Bioactivatable Pseudotripeptidization of Cyclic Dipeptides To Increase the Affinity toward Oligopeptide Transporter 1 for Enhanced Oral Absorption: An Application to Cyclo(L‑Hyp‑L‑Ser) (JBP485)
复制标题
环状二肽的可生物激活假三肽化以增加对寡肽转运蛋白 1 的亲和力以增强口服吸收：在 Cyclo(L–Hyp–L–Ser) 上的应用 (JBP485)
DOI：
10.1021/acs.jmedchem.9b00358
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发表时间：
2019
影响因子：
7.3
通讯作者：
Zhonggui He
中科院分区：
文献类型：
--
作者：
Qikun Jiang;Jiangnan Zhang;Peiyue Tong;Yan Gao;Yiqin Lv;Changyuan Wang;Meiling Luo;Mengchi Sun;Jian Wang;Yao Feng;Linlin Cao;Gang Wang;Yang Wang;Qiming Kan;Tianhong Zhang;Yongjun Wang;Kexin Liu;Jin Sun;Zhonggui He
环状二肽与肠寡肽转运体1(PEPT1)的亲和力一般低于线状二肽。JBP485是一种低亲和力的PEPT1底物，口服生物利用度较低。而JBP923(L-羟基-L-丝氨酸)是PEPT1的高亲和力底物，具有较高的口服吸收能力。我们假设，可生物激活的伪三肽化前药策略有望增加环二肽对PEPT1的亲和力。为了验证我们的假设，我们设计了五种JBP485的氨基酸酯前药。与JBP485相比，优化的前药(JBP485-3-CH2-O-valine，J3V)显示出更好的PEPT1亲和力，在大鼠和比格犬体内的口服生物利用度。此外，J3V对小鼠肝损伤具有剂量依赖性保护作用。此外，J3V在胃肠道中稳定，有利于PEPT1介导的膜转运，并在肠细胞和肝细胞中被激活，这是激发其生物活性所必需的。综上所述，可生物激活的伪三肽化策略在提高PEPT1的亲和力以提高环二肽的口服生物利用度方面显示出潜力。
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-CH2-O-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.