Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine active in the bodily immune response and serious inflammatory diseases. Traditional ligands targeting TNF-α focus on antibodies and receptors, which always associate with low efficacy and specificity. In the present study, two peptide ligands (T1: Ac-RKEM-NH₂ and T2: Ac-RHCLS-NH₂) were designed by computer simulation technology considering the weak interactions between TNF-α and its receptor TNFR1. Calculations of binding free energy (BFE) were made by the Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) method between T1 or T2 and TNF-α (−22.68 and −14.23 kcal mol⁻¹, respectively). To assess the affinity levels, short peptide ligands were fixed on polyvinyl alcohol (PVA) microspheres; adsorption tests showed a stronger affinity of both PVA-T1 and PVA-T2 to TNF-α in PBS buffer than PVA microspheres (79.20 ± 1.32 and 74.27 ± 1.10 vs. 39.03 ± 1.25 pg mg⁻¹, respectively). Moreover, PVA-T1 (74.8%, 17.60 ± 2.98 pg mg⁻¹) and PVA-T2 (63.2%, 15.30 ± 4.81 pg mg⁻¹) exhibit significantly enhanced TNF-α adsorption from the plasma of rats with sepsis to blank PVA and commercial XAD-7 resin. In conclusion, our results show that T1 designed by computer-aided molecular design (CAMD) exhibits a stronger affinity to TNF-α and it can significantly enhance PVA microsphere adsorption efficiency of TNF-α in plasma.

中文翻译：

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针对吸附剂应用的靶向肿瘤坏死因子-α的短肽配体的计算机辅助设计†

肿瘤坏死因子α（TNF-α）是一种在身体免疫反应和严重炎症疾病中活跃的促炎细胞因子。靶向TNF-α的传统配体专注于抗体和受体，这些抗体和受体总是与低功效和特异性相关。在本研究中，考虑到TNF-α及其受体TNFR1之间的弱相互作用，通过计算机模拟技术设计了两个肽配体（T1：Ac-RKEM-NH ₂和T2：Ac-RHCLS-NH ₂）。通过分子力学泊松-玻尔兹曼表面积（MM-PBSA）方法计算T1或T2与TNF-α之间的结合自由能（BFE）（−22.68和-14.23 kcal mol ^-1， 分别）。为了评估亲和力水平，将短肽配体固定在聚乙烯醇（PVA）微球上；吸附测试表明，PVA-T1和PVA-T2对PBS缓冲液中的TNF-α的亲和力均高于PVA微球（分别为79.20±1.32和74.27±1.10，而39.03±1.25 pg mg ^-1）。此外，PVA-T1（74.8％，17.60±2.98 pg mg ^-1）和PVA-T2（63.2％，15.30±4.81 pg mg ^-1）从脓毒症大鼠血浆到空白PVA的TNF-α吸附显着增强。和商业XAD-7树脂。总之，我们的结果表明，通过计算机辅助分子设计（CAMD）设计的T1对TNF-α表现出更强的亲和力，并且可以显着提高血浆中TNF-α的PVA微球吸附效率。