Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA.
Molecules. 2019 Sep 27;24(19):3512. doi: 10.3390/molecules24193512.
Cancer vaccine is a promising immunotherapeutic approach to train the immune system with vaccines to recognize and eliminate tumors. Adjuvants are compounds that are necessary in cancer vaccines to mimic an infection process and amplify immune responses. The Toll-like receptor 2 and 6 (TLR2/TLR6) agonist dipalmitoyl--glyceryl cysteine (PamCys) was demonstrated as an ideal candidate for synthetic vaccine adjuvants. However, the synthesis of PamCys requires expensive -protected cysteine as a key reactant, which greatly limits its application as a synthetic vaccine adjuvant in large-scaled studies. Here, we report the development of N-acetylated PamCys analogs as TLR2/TLR6 agonists. Instead of -protected cysteine, the synthesis utilizes -acetylcysteine to bring down the synthetic costs. The -acetylated PamCys analogs were demonstrated to activate TLR2/TLR6 in vitro. Moreover, molecular docking studies were performed to provide insights into the molecular mechanism of how N-acetylated PamCys analogs bind to TLR2/TLR6. Together, these results suggest -acetylated PamCys analogs as inexpensive and promising synthetic vaccine adjuvants to accelerate the development of cancer vaccines in the future.
癌症疫苗是一种有前途的免疫治疗方法，它可以利用疫苗训练免疫系统识别和消除肿瘤。佐剂是癌症疫苗中必需的化合物，可模拟感染过程并增强免疫反应。Toll 样受体 2 和 6（TLR2/TLR6）激动剂二棕榈酰基甘氨酰半胱氨酸（PamCys）已被证明是合成疫苗佐剂的理想候选物。然而，PamCys 的合成需要昂贵的保护半胱氨酸作为关键反应物，这极大地限制了其作为合成疫苗佐剂在大规模研究中的应用。在这里，我们报告了 N-乙酰化 PamCys 类似物作为 TLR2/TLR6 激动剂的开发。该合成方法利用 -乙酰半胱氨酸代替 -保护半胱氨酸，降低了合成成本。N-乙酰化 PamCys 类似物在体外被证明能激活 TLR2/TLR6。此外，还进行了分子对接研究，以深入了解 N-乙酰化 PamCys 类似物与 TLR2/TLR6 结合的分子机制。总之，这些结果表明 N-乙酰化 PamCys 类似物是一种廉价且有前途的合成疫苗佐剂，有望加速未来癌症疫苗的开发。
