Third World Center for Science and Technology, H.E.J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Bioorg Chem. 2022 Jul;124:105841. doi: 10.1016/j.bioorg.2022.105841. Epub 2022 Apr 27.
The cyclic peptide stylissatin A(STA) was obtained from the Papua New Guinean marine spongeStylissamassaas a potent nitric oxide (NO) inhibitor.Among its reported analogs,cyclo-{Glu, Ala}-STA1potentlyinhibited theinterleukin-2 and proliferation of T-cells indicating position 2 of sequence playing important part in biological activities of this compound.In current studies, second generation analogs of STAwere synthesizedaround its most active analog1by screening position 2 of analog1with different amino acid. All analogs2-6were identified by mass, and NMR techniques.The synthesized analogswere also evaluated against NO generation by lipopolysaccharide (LPS)-stimulated murine J774.2macrophages, ROS inhibition from whole blood phagocytes, and T-cell proliferation from Jurkat cells.All analogswere found to be inactive towards interleukin-2, T-cells proliferation, and ROS inhibition. The analog2showed a potent suppression of NO (IC = 46.0 ± 2.2 µM) that was superior to the activityreported for natural product STA.Further attempts to optimizeanalog2afforded new nitric oxide inhibitors2a-2fwhich were found less active than2.The analog2also downregulated the transcription of pro-inflammatory molecules, tumor necrosis factor-α, interlukin-1β, caspase-1 and ASC which further highlights its anti-inflammatory and possible therapeutic potential. Analog2was non-toxic to BJ and Vero cell lines of normal mammalian origin.
环肽 stylissatin A（STA）是从巴布亚新几内亚海洋海绵Stylissamassa 中获得的，是一种有效的一氧化氮（NO）抑制剂。在其报道的类似物中，cyclo-{Glu, Ala}-STA1 强烈抑制白细胞介素-2 和 T 细胞的增殖，表明序列的 2 位在该化合物的生物活性中起着重要作用。在当前的研究中，通过筛选类似物 1 的 2 位，用不同的氨基酸合成了 STA 的第二代类似物。所有类似物 2-6 均通过质谱和 NMR 技术鉴定。还评估了合成类似物对脂多糖（LPS）刺激的鼠 J774.2 巨噬细胞中 NO 的生成、全血吞噬细胞中 ROS 的抑制以及 Jurkat 细胞中 T 细胞的增殖。所有类似物对白细胞介素-2、T 细胞增殖和 ROS 抑制均无活性。类似物 2 显示出对 NO 的强烈抑制作用（IC=46.0±2.2µM），优于天然产物 STA 的活性。进一步优化类似物 2 的尝试提供了新的一氧化氮抑制剂 2a-2f，其活性低于 2。类似物 2 还下调了促炎分子肿瘤坏死因子-α、白细胞介素-1β、半胱天冬酶-1 和 ASC 的转录，这进一步突出了其抗炎和潜在的治疗潜力。类似物 2 对来源于正常哺乳动物的 BJ 和 Vero 细胞系无毒性。
