Esterase-sensitive cyclic prodrugs of peptides: evaluation of an acyloxyalkoxy promoiety in a model hexapeptide.
Esterase-sensitive cyclic prodrugs of peptides: evaluation of an acyloxyalkoxy promoiety in a model hexapeptide.
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肽的酯酶敏感的环状前药：模型六肽中酰氧基烷氧基前体的评估。
DOI：
10.1023/a:1016472119387
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发表时间：
1996
影响因子：
3.7
通讯作者：
Borchardt,RT
中科院分区：
文献类型：
--
作者：
Pauletti,GM;Gangwar,S;Okumu,FW;Siahaan,TJ;Stella,VJ;Borchardt,RT
目的。研究了一种新型的环酰基氧基氨基甲酸酯前药（H-Trp-Ala-Gly-Gly-Asp-Ala-OH），以提高模型六肽的膜透性，稳定其代谢。在37°C的缓冲水溶液和具有可测量的酯酶活性的各种生物环境中，研究了向线性六肽的转化。使用Caco-2细胞培养模型评估转运和代谢特性。在缓冲溶液中，环状前药在化学上降解为化学计量量的线性六肽。pH值在3-4之间达到最大稳定性。在90%人血浆（t1/2= 100±4 min）、大鼠肠粘膜匀浆（t-= 136±4 min）和大鼠肝脏匀浆（t-= 65±3 min）中，环前药的消失速度快于pH 7.4缓冲液（t-= 206±11 min）。用对氧磷预处理这些培养基可显著降低前药的降解率。当作用于cco -2细胞单分子层的顶侧时，环前药（t-= 282±25 min）的稳定性显著高于六肽（t-= 14 min），其渗透能力（Papp= 1.30±0.15 × 10−7cm/ s）至少是亲本肽（Papp≤0.17 × 10−8cm/s）的76倍。使用酰基烷氧基促进基团制备的环状肽降低了肽对肽酶代谢的不稳定性，并大大增加了其通过生物膜的渗透。在各种生物培养基中，母体肽通过明显的酯酶催化反应从前药中释放出来，对对氧抑制敏感。
Purpose. To evaluate a cyclic acyloxyalkoxycarbamate prodrug of a model hexapeptide (H-Trp-Ala-Gly-Gly-Asp-Ala-OH) as a novel approach to enhance the membrane permeation of the peptide and stabilize it to metabolism.Methods. Conversion to the linear hexapeptide was studied at 37°C in aqueous buffered solutions and in various biological milieus having measurable esterase activities. Transport and metabolism characteristics were assessed using the Caco-2 cell culture model.Results. In buffered solutions the cyclic prodrug degraded chemically to the linear hexapeptide in stoichiometric amounts. Maximum stability was observed between pH 3–4. In 90% human plasma (t1/2= 100 ± 4 min) and in homogenates of the rat intestinal mucosa (t-= 136 ± 4 min) and rat liver (t-= 65 ± 3 min), the cyclic prodrug disappeared faster than in buffered solution, pH 7.4 (t-= 206 ± 11 min). Pretreatment of these media with paraoxon significantly decreased the degradation rate of the prodrug. When applied to the apical side of Caco-2 cell monolayers, the cyclic prodrug (t-= 282 ± 25 min) was significantly more stable than the hexapeptide (t-= 14 min) and at least 76-fold more able to permeate (Papp= 1.30 ± 0.15 × 10−7cm/ s) than the parent peptide (Papp≤ 0.17 × 10−8cm/s).Conclusions. Preparation of a cyclic peptide using an acyloxyalkoxy promoiety reduced the lability of the peptide to peptidase metabolism and substantially increased its permeation through biological membranes. In various biological media the parent peptide was released from the prodrug by an apparent esterase-catalyzed reaction, sensitive to paraoxon inhibition.