A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.
A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.
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DOI：
10.1021/acs.bioconjchem.6b00209
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发表时间：
2016-07-20
影响因子：
4.7
通讯作者：
Thurber GM
中科院分区：
文献类型：
--
作者：
Zhang L;Navaratna T;Thurber GM
稳定的肽解决了基于肽的成像剂和治疗剂的几个限制，例如由于构象柔性导致的差的稳定性和低亲和力。在开发这些化合物用于细胞内药物靶向方面也有积极的研究，并且已经投入了大量的努力来确定螺旋稳定化对细胞内递送的影响。然而，对其他药代动力学参数（如血浆清除率和生物利用度）的影响知之甚少。我们使用胰高血糖素样肽-1（GLP-1）受体配体exendin作为模型系统，研究了具有不同亲脂性的不同荧光螺旋稳定连接体对皮下（SC）生物利用度的影响。稳定化的肽显示出显著更高的蛋白酶抗性和增加的生物利用度，与接头亲水性无关，并且所有皮下递送的缀合物都能够以高特异性成功靶向胰岛。亲脂性肽变体的吸收和血浆清除率低于其各自的亲水性缀合物，并且绝对生物利用度也可能较低，这可能是由于在皮肤中的停留时间较长。双击螺旋稳定化化学的简易性和效率是用于增加肽治疗剂的生物利用度的有用工具，其中许多肽治疗剂遭受快速的体内蛋白酶降解。使用不同亲脂性的接头的受阻稳定化可以进一步控制SC吸收和清除速率以定制血浆药代动力学。
Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (SC) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. The ease and efficiency of double-click helix stabilization chemistries is a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control SC absorption and clearance rates to customize plasma pharmacokinetics.