Solid-Phase Synthesis of the Bicyclic Peptide OL-CTOP Containing Two Disulfide Bridges, and an Assessment of Its In Vivo μ-Opioid Receptor Antagonism after Nasal Administration.
Solid-Phase Synthesis of the Bicyclic Peptide OL-CTOP Containing Two Disulfide Bridges, and an Assessment of Its In Vivo μ-Opioid Receptor Antagonism after Nasal Administration.
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DOI：
10.3390/molecules28041822
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发表时间：
2023-02-15
期刊：
影响因子：
4.6
通讯作者：
Cudic, Predrag
中科院分区：
文献类型：
--
作者：
Rayala, Ramanjaneyulu;Tiller, Annika;Majumder, Shahayra A. A.;Stacy, Heather M. M.;Eans, Shainnel O. O.;Nedovic, Aleksandra;McLaughlin, Jay P. P.;Cudic, Predrag
关键词：
新的策略促进了环肽的设计，这些环肽可以穿透大脑。我们设计了一种由选择性μ阿片受体拮抗剂CTOP(f-Cyclo(CywOTX)T)(X=青霉胺，PEN；O=鸟氨酸)和Oorranalectin，OL(YASPK-Cyclo(CFRYPNGVLAC)T)序列组成的双环肽OL-CTOP，并对其固相合成进行了优化，证明了其经鼻向脑递送和体内活性的能力。利用在不同溶剂中用三苯基和/或乙酰氨基甲基保护基团保护的Cys和Pen硫醇基团对I2的反应活性的差异，在固相上选择性地形成二硫键。应用于大环化反应的单步和序贯策略都产生了所需的OL-CTOP，其中序贯策略产生了大量和更高纯度的粗品OL-CTOP。重要的是，鼻腔(I.N.S.)给予OL-CTOP可剂量依赖性地拮抗小鼠脑室注射吗啡的镇痛作用，并可阻止吗啡引起的呼吸抑制。综上所述，这些结果证明了我们的固相合成策略用于制备含有两个二硫键的OL-CTOP双环肽的可行性，并揭示了气味凝集素进一步修饰和定向输送到大脑的潜力。
New strategies facilitate the design of cyclic peptides which can penetrate the brain. We have designed a bicyclic peptide, OL-CTOP, composed of the sequences of a selective μ-opioid receptor antagonist, CTOP (f-cyclo(CYwOTX)T) (X = penicillamine, Pen; O = ornithine) and odorranalectin, OL (YASPK-cyclo(CFRYPNGVLAC)T), optimized its solid-phase synthesis and demonstrated its ability for nose-to-brain delivery and in vivo activity. The differences in reactivity of Cys and Pen thiol groups protected with trityl and/or acetamidomethyl protecting groups toward I2 in different solvents were exploited for selective disulfide bond formation on the solid phase. Both the single step and the sequential strategy applied to macrocyclization reactions generated the desired OL-CTOP, with the sequential strategy yielding a large quantity and better purity of crude OL-CTOP. Importantly, intranasally (i.n.s.) administered OL-CTOP dose-dependently antagonized the analgesic effect of morphine administered to mice through the intracerebroventricular route and prevented morphine-induced respiratory depression. In summary, the results demonstrate the feasibility of our solid-phase synthetic strategy for the preparation of the OL-CTOP bicyclic peptide containing two disulfide bonds and reveal the potential of odorranalectin for further modifications and the targeted delivery to the brain.
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影响因子：
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作者：
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