PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma is the most prevalent pancreatic cancer, which is considered a significant global health concern. Chemotherapy and surgery are the mainstays of current pancreatic cancer treatments; however, a few cases are suitable for surgery, and most of the cases will experience recurrent episodes. Compared to DNA or peptide vaccines, mRNA vaccines for pancreatic cancer have more promise because of their delivery, enhanced immune responses, and lower proneness to mutation. We constructed an mRNA vaccine by analyzing S100 family proteins, which are all major activators of receptors for advanced glycation end products. We applied immunoinformatic approaches, including physicochemical properties analysis, structural prediction and validation, molecular docking study, in silico cloning, and immune simulations. The designed mRNA vaccine was estimated to have a molecular weight of 165023.50 Da and was highly soluble (grand average of hydropathicity of -0.440). In the structural assessment, the vaccine seemed to be a well-stable and functioning protein (Z score of -8.94). Also, the docking analysis suggested that the vaccine had a high affinity for TLR-2 and TLR-4 receptors. Additionally, the molecular mechanics with generalized Born and surface area solvation analysis of the \"Vaccine-TLR-2\" (-141.07 kcal/mol) and \"Vaccine-TLR-4\" (-271.72 kcal/mol) complexes also suggests a strong binding affinity for the receptors. Codon optimization also provided a high expression level with a GC content of 47.04% and a codon adaptation index score 1.0. The appearance of memory B-cells and T-cells was also observed over a while, with an increased level of helper T-cells and immunoglobulins (IgM and IgG). Moreover, the minimum free energy of the mRNA vaccine was predicted at -1760.00 kcal/mol, indicating the stability of the vaccine following its entry, transcription, and expression. This hypothetical vaccine offers a groundbreaking tool for future research and therapeutic development of pancreatic cancer.
摘要：
胰腺导管腺癌是最常见的胰腺癌,这被认为是一个重大的全球健康问题。化疗和手术是目前胰腺癌治疗的支柱;然而，少数病例适合手术，大多数病例会反复发作。与DNA或肽疫苗相比，胰腺癌的mRNA疫苗有更多的希望，因为它们的递送，增强的免疫反应，和较低的倾向于突变。我们通过分析S100家族蛋白构建了一种mRNA疫苗，它们都是晚期糖基化终产物受体的主要激活剂。我们应用了免疫信息学方法，包括物理化学性质分析，结构预测和验证，分子对接研究,硅克隆，和免疫模拟。估计设计的mRNA疫苗具有165023.50Da的分子量,并且是高度可溶的(亲水性的总平均值为-0.440)。在结构评估中，该疫苗似乎是一种稳定且功能良好的蛋白质(Z评分为-8.94).此外，对接分析表明,该疫苗对TLR-2和TLR-4受体具有高亲和力.此外,对“疫苗-TLR-2”（-141.07kcal/mol）和“疫苗-TLR-4”（-271.72kcal/mol）复合物进行广义Born和表面积溶剂化分析的分子力学也表明对受体具有很强的结合亲和力。密码子优化还提供了高表达水平,GC含量为47.04%,密码子适应指数评分为1.0。在一段时间内还观察到记忆B细胞和T细胞的出现，辅助性T细胞和免疫球蛋白（IgM和IgG）水平升高。此外，mRNA疫苗的最小自由能预测为-1760.00kcal/mol，表明疫苗进入后的稳定性，转录,和表情。这种假设的疫苗为胰腺癌的未来研究和治疗发展提供了开创性的工具。
