La Manna Sara, Leone Marilisa, Mercurio Flavia Anna, Florio Daniele, Marasco Daniela
Department of Pharmacy, Research Center on Bioactive Peptides (CIRPEB), University of Naples "Federico II", 80131 Naples, Italy.
Institute of Biostructures and Bioimaging (CNR), 80145 Naples, Italy.
Pharmaceuticals (Basel). 2022 Apr 9;15(4):458. doi: 10.3390/ph15040458.
SOCS3 (suppressor of cytokine signaling 3) protein suppresses cytokine-induced inflammation and its deletion in neurons or immune cells increases the pathological growth of blood vessels. Recently, we designed several SOCS3 peptidomimetics by assuming as template structures the interfacing regions of the ternary complex constituted by SOCS3, JAK2 (Janus Kinase 2) and gp130 (glycoprotein 130) proteins. A chimeric peptide named KIRCONG chim, including non-contiguous regions demonstrated able to bind to JAK2 and anti-inflammatory and antioxidant properties in VSMCs (vascular smooth muscle cells). With the aim to improve drug-like features of KIRCONG, herein we reported novel cyclic analogues bearing different linkages. In detail, in two of them hydrocarbon cycles of different lengths were inserted at positions i/i+5 and i/i+7 to improve helical conformations of mimetics. Structural features of cyclic compounds were investigated by CD (Circular Dichroism) and NMR (Nuclear Magnetic Resonance) spectroscopies while their ability to bind to catalytic domain of JAK2 was assessed through MST (MicroScale Thermophoresis) assay as well as their stability in biological serum. Overall data indicate a crucial role exerted by the length and the position of the cycle within the chimeric structure and could pave the way to the miniaturization of SOCS3 protein for therapeutic aims.
细胞因子信号转导抑制因子3（SOCS3）蛋白可抑制细胞因子诱导的炎症反应，其在神经元或免疫细胞中的缺失会增加血管的病理性生长。最近，我们以SOCS3、Janus激酶2（JAK2）和糖蛋白130（gp130）蛋白构成的三元复合物的界面区域为模板结构，设计了几种SOCS3拟肽。一种名为KIRCONG chim的嵌合肽，包括非连续区域，被证明能够与JAK2结合，并在血管平滑肌细胞（VSMC）中具有抗炎和抗氧化特性。为了改善KIRCONG的类药物特性，我们在此报告了带有不同连接键的新型环状类似物。具体而言，在其中两种类似物中，在i/i + 5和i/i + 7位置插入了不同长度的烃环，以改善模拟物的螺旋构象。通过圆二色性（CD）光谱和核磁共振（NMR）光谱研究了环状化合物的结构特征，同时通过微量热泳（MST）分析评估了它们与JAK2催化结构域结合的能力以及它们在生物血清中的稳定性。总体数据表明，嵌合结构中环的长度和位置发挥了关键作用，这可能为治疗目的的SOCS3蛋白小型化铺平道路。
