Rheumatoid arthritis disease is a chronic auto-immune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. The tumor necrosis factor-α (TNF-α) is a pivotal cytokine that plays an important role in rheumatoid arthritis. The treatments focusing on a single cytokine inhibition are clinically able to produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bispecific tandem single-chain variable fragment was designed in order to suppress both human tumor necrosis factor-α and interleukin-23 (IL23) as a potential therapeutic drug candidate for this disease. To do so, at first, eight bispecific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders by the homology modeling, and then 50 ns molecular dynamics simulation was performed for each one and then structural properties were exploited. The MD simulation results indicate the fact that the domains’ order strongly affects tandem single-chain variable fragment properties, and in overall, the fragment V_LAIL23+Linker+V_HAIL23+linker+V_LATNF+Linker +V_HATNF +His6 (V_L and V_H are light and heavy chain variable fragments and AIL23 and ATNF are anti-interleukin 23 and anti-tumor necrosis factor-α, respectively, and His6 is the six histidine) not only separated antibody domains accurately but also had better stability and solvation free energy. Therefore, this structure can be considered as an effective potential drug for rheumatoid arthritis. It is expected that the findings of this research could shed a light on the treatment approaches of the rheumatoid arthritis disease.

中文翻译：

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使用计算机研究研究类风湿性关节炎，设计一种针对肿瘤坏死因子-α和白介素-23的新型双特异性串联单链可变片段抗体。

类风湿关节炎疾病是一种慢性自身免疫性炎性疾病，主要引起滑膜关节发炎和软骨破坏。肿瘤坏死因子-α（TNF-α）是关键的细胞因子，在类风湿关节炎中起重要作用。由于涉及该疾病的多种细胞因子，临床上专注于单一细胞因子抑制的治疗仅能在大约一半的治疗患者中产生有意义的反应。在本研究中，设计了双特异性串联单链可变片段，以抑制人类肿瘤坏死因子-α和白介素-23（IL23）作为该疾病的潜在治疗药物。为此，首先 通过同源性建模，建立了针对不同域顺序的肿瘤坏死因子-α和白介素-23细胞因子的8种双特异性串联单链可变片段模型，然后分别进行了50 ns的分子动力学模拟，并利用其结构特性进行了研究。MD模拟结果表明，域的顺序会强烈影响串联单链可变片段的性质，整体上会影响片段V_大号AIL23 +接头+ V _ħ AIL23 +接头+ V_大号ATNF +接头+ V _ħ ATNF +的His6（V_大号和V _ħ是轻链和重链可变片段和AIL23和ATNF是抗白介素23和抗肿瘤坏死因子-α和His6是六个组氨酸）不仅可以准确地分离抗体结构域，而且具有更好的稳定性和溶剂化自由能。因此，该结构可以被认为是类风湿关节炎的有效潜在药物。预期该研究的结果将为类风湿关节炎疾病的治疗方法提供启示。