How structural features influence the biomembrane permeability of peptides
How structural features influence the biomembrane permeability of peptides
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DOI：
10.1021/js960067d
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发表时间：
1996-12-01
影响因子：
3.8
通讯作者：
Borchardt, RT
中科院分区：
文献类型：
--
作者：
Burton, PS;Conradi, RA;Borchardt, RT
成功的药物开发不仅需要优化靶点的特异性和有效的药理学活性，还需要有效地递送到该位点。已经鉴定了许多具有治疗AIDS、心血管疾病和CNS疾病的新治疗潜力的有前途的新肽，但是它们的临床应用受到递送问题的限制。沿着代谢，认为导致肽的生物利用度差的主要因素是跨细胞膜的低效转运。目前，人们对这种运输状况不佳的原因知之甚少。为了探索这个问题，我们设计了实验，重点是确定肽结构和肽在体外和体内跨各种生物膜的转运之间的关系。简而言之，制备了在链长、亲脂性和酰胺键数方面系统变化的肽。这些溶质的渗透性结果支持一种模型，其中肽转运的主要决定因素是肽中极性酰胺去溶剂化所需的能量，以使肽进入并扩散穿过细胞膜。对肽渗透性的进一步影响是存在于肠上皮细胞和脑内皮细胞的顶膜中的活性分泌转运系统的存在。在Caco-2细胞单层（人肠粘膜模型）中，该途径显示底物特异性、饱和和抑制。在大鼠肠和血脑屏障吸收模型中，体内均显示出相似的结果。这种系统的存在通过将一部分吸收的肽返回到管腔而充当额外的转运屏障。
Successful drug development requires not only optimization of specific and potent pharmacological activity at the target site, but also efficient delivery to that site. Many promising new peptides with novel therapeutic potential for the treatment of AIDS, cardiovascular diseases, and CNS disorders have been identified, yet their clinical utility has been limited by delivery problems. Along with metabolism, a major factor contributing to the poor bioavailability of peptides is thought to be inefficient transport across cell membranes. At the present time, the reasons for this poor transport are poorly understood. To explore this problem, we have designed experiments focused on determining the relationship between peptide structure and peptide transport across various biological membranes both in vitro and in vivo. Briefly, peptides that varied systematically in chain length, lipophilicity, and amide bond number were prepared. Permeability results with these solutes support a model in which the principal determinant of peptide transport is the energy required to desolvate the polar amides in the peptide for the peptide to enter and diffuse across the cell membrane. Further impacting on peptide permeability is the presence of active, secretory transport systems present in the apical membrane of intestinal epithelial and brain endothelial cells. In Caco-2 cell monolayers, a model of the human intestinal mucosa, this pathway displayed substrate specificity, saturation, and inhibition. Similar results have been shown in vivo in both rat intestinal and blood-brain barrier absorption models. The presence of such systems serves as an additional transport barrier by returning a fraction of absorbed peptide back to the lumen.