最近描述了环-[Pro-Pro-β3-HoPhe-Phe-]四肽（表示为4B8M）的抗炎、抗病毒和抗癌特性以及作用机制。这项工作的目的是使用母体 4B8M 作为参考化合物，通过 D-氨基酸（一系列表示为 P01-P07 的肽）顺序取代 L-氨基酸，合成并评估 4B8M 立体化学变体的免疫抑制作用。此外，还测试了使用机器学习和人工智能的多种可用生物信息学工具，以发现分析的立体异构体的生物药代动力学和多药理学属性。所有肽对人外周血单核细胞 (PBMC) 均无毒，只有环-[D-Pro-Pro-β3-HoPhe-Phe-] 肽 (P03) 能够抑制丝裂原诱导的 PBMC 增殖。这些肽在不同程度上抑制脂多糖（LPS）诱导的肿瘤坏死因子-α（TNF-α）的产生，其中 P04（环-[Pro-Pro-D-β3-HoPhe-Phe-]）和 P03 是最有力的。对于进一步的体内研究，选择 P03 是因为它具有抑制细胞增殖和 TNF-α 产生的综合特性。 P03 在抑制耳廓水肿和淋巴结细胞数量以及使恶唑酮小鼠模型接触敏感性中扭曲的血细胞组成正常化方面表现出与 4B8M 相当的能力。在角叉菜胶诱导的气囊炎症小鼠模型中，P03对气囊中细胞数量的抑制作用与4B8M相似，但其对气囊和血液中中性粒细胞和嗜酸性粒细胞百分比的抑制作用也相同。与 4B8M 相比，气囊中的肥大细胞脱粒作用更强。最后，在硫酸葡聚糖诱导的结肠炎小鼠模型中，在胸腺细胞数量恢复和 P03 血细胞图像正常化方面观察到与 4B8M 类似的效果。总之，根据实验结果或计算机预测，P03 表现出与 4B8M 相当甚至更好的抗炎和生物药代动力学特性，可被视为一种潜在的治疗方法。通过量子化学计算测试了通过圆二色性测量识别 P00 和 P03 的可能性。

The anti-inflammatory, antiviral, and anti-cancer properties, as well as the mechanism of action of cyclo-[Pro-Pro-β3-HoPhe-Phe-] tetrapeptide (denoted as 4B8M), were recently described. The aim of this work was to synthesize and evaluate the immunosuppressive actions of the stereochemical variants of 4B8M by sequential substitution of L-amino acids by D-amino acids (a series of peptides denoted as P01-P07) using parent 4B8M as a reference compound. In addition, diverse available bioinformatics tools using machine learning and artificial intelligence were tested to find the bio-pharmacokinetic and polypharmacological attributes of analyzed stereomers. All peptides were non-toxic to human peripheral blood mononuclear cells (PBMCs) and only cyclo-[D-Pro-Pro-β3-HoPhe-Phe-] peptide (P03) was capable of inhibiting mitogen-induced PBMC proliferation. The peptides inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) to various degrees, with P04 (cyclo-[Pro-Pro-D-β3-HoPhe-Phe-]) and P03 being the most potent. For further in vivo studies, P03 was selected because it had the combined properties of inhibiting cell proliferation and TNF-α production. P03 demonstrated a comparable ability to 4B8M in the inhibition of auricle edema and lymph node cell number and in the normalization of a distorted blood cell composition in contact sensitivity to the oxazolone mouse model. In the mouse model of carrageenan-induced inflammation of the air pouch, P03 exhibited a similar inhibition of the cell number in the air pouches as 4B8M, but its inhibitory effects on the percentage of neutrophils and eosinophils in the air pouches and blood, as well as on mastocyte degranulation in the air pouches, were stronger in comparison to 4B8M. Lastly, in a mouse model of dextran sulfate-induced colitis, similar effects to 4B8M regarding thymocyte number restoration and normalization of the blood cell pictures by P03 were observed. In summary, depending on either experimental findings or in silico predictions, P03 demonstrated comparable, or even better, anti-inflammatory and bio-pharmacokinetic properties to 4B8M and may be considered as a potential therapeutic. The possibility of P00 and P03 identification by circular dichroism measurements was tested by quantum-chemical calculations.