Geranurimi Azade, Cheng Colin W H, Quiniou Christiane, Côté France, Hou Xin, Lahaie Isabelle, Boudreault Amarilys, Chemtob Sylvain, Lubell William D
Département de Chimie, Université de Montréal, Montréal, QC, Canada.
Department of Pharmacology & Therapeutics, McGill University, Montréal, QC, Canada.
Front Chem. 2020 Dec 21;8:610431. doi: 10.3389/fchem.2020.610431. eCollection 2020.
As a key cytokine mediator of inflammation, interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) and activates various downstream signaling mediators, including NF-κB, which is required for immune vigilance and cellular protection. Toward the development of IL-1-targeting therapeutics which exhibit functional selectivity, the all-D-amino acid peptide (101.10, H-D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala-NH) was conceived as an allosteric IL-1R modulator that conserves NF-κB signaling while inhibiting other IL-1-activated pathways. Employing β-hydroxy-α-amino-γ-lactam (Hgl) stereoisomers to study the conformation about the Thr residue in , [(3,4)-Hgl]- (), among all possible diastereomers, was found to exhibit identical and activity as the parent peptide and superior activity to the α-amino-γ-lactam (Agl) counterpart. Noting the relevance of the β-hydroxyl substituent and configuration for the activity of (3,4)-, fifteen different β-substituted-Agl analogs of (e.g., ) have now been synthesized by a combination of solution- and solid-phase methods employing -Fmoc-β-substituted-Agl-Val-OH dipeptide building blocks. Introduction of a β-azido-Agl residue into the resin bound peptide and subsequent reduction and CuAAC chemistry gave access to a series of amine and triazole derivatives (e.g., ). β-Substituted-[Agl]- analogs exhibited generally similar circular dichroism (CD) spectra as that of Hgl analog in water, presenting curve shapes indicative of β-turn structures. The relevance of the β-substituent was indicated in rodent models of preterm labor and retinopathy of prematurity (ROP), in which certain analogs inhibited preterm birth and vaso-obliteration, respectively, with activity similar to and . The β-substituted-[Agl]- analogs exhibited functional selectivity on IL-1-induced signaling pathways. The described solid-phase method has provided discerning probes for exploring peptide structure-activity relationships and valuable leads for developing prototypes to treat inflammatory events leading to prematurity and retinopathy of prematurity, which are leading causes of infant morbidity and blindness respectively.
作为炎症的关键细胞因子介质，白细胞介素-1β（IL-1β）与IL-1受体（IL-1R）结合并激活各种下游信号介质，包括免疫警戒和细胞保护所需的NF-κB。为了开发具有功能选择性的IL-1靶向疗法，全D-氨基酸肽（101.10，H-D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala-NH）被设想为一种变构IL-1R调节剂，它在抑制其他IL-1激活途径的同时保留NF-κB信号传导。利用β-羟基-α-氨基-γ-内酰胺（Hgl）立体异构体研究101.10中苏氨酸残基的构象，在所有可能的非对映异构体中，[(3,4)-Hgl]-101.10（101.10-Hgl）被发现与母体肽表现出相同的体外和体内活性，并且比α-氨基-γ-内酰胺（Agl）对应物具有更高的活性。注意到β-羟基取代基和构型与(3,4)-101.10活性的相关性，现在已经通过使用-Fmoc-β-取代-Agl-Val-OH二肽构建块的溶液相和固相方法相结合，合成了15种不同的β-取代-Agl类似物（例如101.10-Agl）。将β-叠氮基-Agl残基引入树脂结合肽中，随后进行还原和CuAAC化学反应，得到了一系列胺和三唑衍生物（例如101.10-Az）。β-取代-[Agl]-101.10类似物在水中的圆二色性（CD）光谱通常与Hgl类似物101.10-Hgl相似，呈现出指示β-转角结构的曲线形状。β-取代基的相关性在早产和早产儿视网膜病变（ROP）的啮齿动物模型中得到了体现，其中某些类似物分别抑制早产和血管闭塞，活性与101.10-Hgl和101.1相同。β-取代-[Agl]-101.10类似物在IL-1诱导的信号通路中表现出功能选择性。所描述的固相方法为探索肽结构-活性关系提供了有鉴别力的探针，并为开发治疗导致早产和早产儿视网膜病变的炎症事件的原型提供了有价值的线索，早产和早产儿视网膜病变分别是婴儿发病和失明的主要原因。
