Prokai-Tatrai Katalin, De La Cruz Daniel L, Nguyen Vien, Ross Benjamin P, Toth Istvan, Prokai Laszlo
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
School of Pharmacy, The University of Queensland, Brisbane, QLD 4072, Australia.
Pharmaceutics. 2019 Jul 18;11(7):349. doi: 10.3390/pharmaceutics11070349.
Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug based on this design principle was synthesized, and its membrane affinity and in vitro metabolic stability, with or without the presence of a POP inhibitor, were studied. The in vivo formation of TRH from the prodrug construct was probed by utilizing the antidepressant effect of the peptide, as well as its ability to increase acetylcholine (ACh) synthesis and release. We found that the prototype prodrug showed excellent membrane affinity and greatly increased metabolic stability in mouse blood and brain homogenate compared to the parent peptide, yet a POP inhibitor completely prevented prodrug metabolism in brain homogenate. In vivo, administration of the prodrug triggered antidepressant-like effect, and microdialysis sampling showed greatly increased ACh release that was also antagonized upon a POP inhibitor treatment. Altogether, the obtained promising exploratory data warrant further investigations on the utility of the prodrug approach introduced here for brain-enhanced delivery of small peptides with neurotherapeutic potential.
以促甲状腺激素释放激素（TRH）为模型，我们探究了脂氨基酸与脯氨酰寡肽酶（POP）裂解的连接子的协同组合是否可作为前药设计的促部分，用于肽的优先脑内递送。基于这一设计原则合成了一种代表性前药，并研究了其在有无POP抑制剂存在下的膜亲和力和体外代谢稳定性。利用该肽的抗抑郁作用及其增加乙酰胆碱（ACh）合成和释放的能力，探究了前药构建体在体内形成TRH的情况。我们发现，与母体肽相比，原型前药在小鼠血液和脑匀浆中表现出优异的膜亲和力和大大提高的代谢稳定性，但POP抑制剂完全阻止了前药在脑匀浆中的代谢。在体内，前药给药引发了类似抗抑郁的作用，微透析采样显示ACh释放大大增加，而POP抑制剂处理也拮抗了这种增加。总之，所获得的有前景的探索性数据保证了对这里引入的前药方法用于具有神经治疗潜力的小肽脑增强递送的效用进行进一步研究。
