Kordopati Golfo G, Tselios Theodore V, Kellici Tahsin, Merzel Franci, Mavromoustakos Thomas, Grdadolnik Simona Golic, Tsivgoulis Gerasimos M
University of Patras, Department of Chemistry, Patras 26504, Greece.
National and Kapodistrian University of Athens, Department of Chemistry, Athens 15771, Greece.
Biochim Biophys Acta. 2015 Jan;1850(1):159-68. doi: 10.1016/j.bbagen.2014.10.017. Epub 2014 Oct 24.
Cyclodextrins (CDs) in combination with therapeutic proteins and other bioactive compounds have been proposed as candidates that show enhanced chemical and enzymatic stability, better absorption, slower plasma clearance and improved dose-response curves or immunogenicity. As a result, an important number of therapeutic complexes between cyclodextrins and bioactive compounds capable to control several diseases have been developed.
In this article, the synthesis and the structural study of a conjugate between a luteinizing hormone-releasing hormone (LHRH) analogue, related to the treatment of hormone dependent cancer and fertility, and modified β-cyclodextrin residue are presented. The results show that both the phenyl group of tyrosine (Tyr) as well as the indole group of tryptophan (Trp) can be encapsulated inside the cyclodextrin cavity. Solution NMR experiments provide evidence that these interactions take place intramolecularly and not intermolecularly.
The study of a LHRH analogue conjugated with modified β-cyclodextrin via high field NMR and MD experiments revealed the existence of intramolecular interactions that could lead to an improved drug delivery.
NMR in combination with MD simulation is of great value for a successful rational design of peptide-cyclodextrin conjugates showing stability against enzymatic proteolysis and a better pharmacological profile.
环糊精（CDs）与治疗性蛋白质及其他生物活性化合物结合后，被认为是具有增强化学和酶稳定性、更好吸收性、更慢血浆清除率以及改善剂量反应曲线或免疫原性的候选物。因此，已开发出大量能够控制多种疾病的环糊精与生物活性化合物之间的治疗性复合物。
本文介绍了一种与激素依赖性癌症治疗和生育相关的促黄体激素释放激素（LHRH）类似物与修饰的β-环糊精残基之间共轭物的合成及结构研究。结果表明，酪氨酸（Tyr）的苯基以及色氨酸（Trp）的吲哚基团均可被包封在环糊精腔内。溶液核磁共振实验提供了证据，证明这些相互作用发生在分子内而非分子间。
通过高场核磁共振和分子动力学实验对与修饰的β-环糊精共轭的LHRH类似物进行的研究揭示了分子内相互作用的存在，这可能导致药物递送得到改善。
核磁共振与分子动力学模拟相结合对于成功合理设计对酶促蛋白水解具有稳定性且具有更好药理学特性的肽-环糊精共轭物具有重要价值。
