Institute of Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Bioorg Med Chem Lett. 2012 Jan 1;22(1):493-6. doi: 10.1016/j.bmcl.2011.10.098. Epub 2011 Nov 4.
Rheumatoid arthritis (RA) is a common human leukocyte antigen-associated disease. Most RA patients have a five-residue sequence motif called the shared epitope (SE) in the DRβ-chain of the HLA-DRB1 protein. The SE was found to activate nitric oxide (NO) production, suggesting a possible mechanism for RA development. The native conformation of the SE is presumed to be an α-helix, thus using cyclic peptides to stabilize this conformation may produce a potent SE mimetic which will have drug-like properties. We present the development of a backbone cyclic SE mimetic that activates NO production in the low nM range. Circular dichroism analysis revealed a conformational change from for the parent linear peptides to the cyclic analogs. The most active cyclic analog is completely stable towards trypsin/chymotrypsin degradation while the linear 15-mer analogs completely degraded within 30 min. The outcome of this study is a potent cyclic peptide with drug-like properties that can be used as a template for drug development.
类风湿关节炎（RA）是一种常见的人类白细胞抗原相关疾病。大多数 RA 患者在 HLA-DRB1 蛋白的 DRβ 链中具有称为共享表位（SE）的五残基序列基序。发现 SE 可激活一氧化氮（NO）的产生，提示 RA 发展的可能机制。SE 的天然构象被假定为α-螺旋，因此使用环状肽稳定这种构象可能会产生具有药物样性质的强效 SE 模拟物。我们提出了一种骨架环状 SE 模拟物的开发，该模拟物在低 nM 范围内激活 NO 的产生。圆二色性分析显示出从亲本线性肽到环状类似物的构象变化。最活跃的环状类似物对胰蛋白酶/糜蛋白酶降解完全稳定，而线性 15 聚体类似物在 30 分钟内完全降解。这项研究的结果是一种具有药物样性质的强效环状肽，可作为药物开发的模板。
