Belz Tyson F, Olson Margaret E, Giang Erick, Law Mansun, Janda Kim D
Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
College of Pharmacy, Roosevelt University, 1400 North Roosevelt Boulevard, Schaumburg, Illinois 60173, United States.
ACS Med Chem Lett. 2020 Oct 29;11(12):2428-2432. doi: 10.1021/acsmedchemlett.0c00413. eCollection 2020 Dec 10.
Hepatitis C virus (HCV) infections represent a global health challenge; however, developing a vaccine for treatment of HCV infection has remained difficult as heterogeneous HCV contains distinct genotypes, and each genotype contains various subtypes and different envelope glycoproteins. Currently, there is no effective preventive vaccine for achieving global control over HCV. In our efforts to improve upon current HCV vaccines we designed a synthetically accessible adjuvant platform, wherein we synthesized 11 novel lipidated tucaresol analogues to assess their immunological potential. Using a tucaresol-based adjuvant approach, truncated lipid-variants together with an engineered E1E2 antigen construct, namely E2ΔTM3, elicited antibody (Ab) responses that were significantly higher than tucaresol. In sum, antibody end-point titer values largely corroborated HCV neutralization data with a simplified lipidated tucaresol variant affording the highest end point titer and % neutralization. This study lays the groundwork for additional permutations in tucaresol adjuvant design, including the examination of other proteins in vaccine development.
丙型肝炎病毒（HCV）感染是一项全球性的健康挑战；然而，开发用于治疗HCV感染的疫苗一直很困难，因为异质性的HCV包含不同的基因型，且每种基因型包含多种亚型和不同的包膜糖蛋白。目前，尚无实现全球控制HCV的有效预防性疫苗。在我们改进现有HCV疫苗的努力中，我们设计了一个合成可达的佐剂平台，在此平台上我们合成了11种新型的脂化土曲霉酚类似物，以评估它们的免疫潜力。采用基于土曲霉酚的佐剂方法，截短的脂质变体与一种工程化的E1E2抗原构建体（即E2ΔTM3）一起引发的抗体（Ab）反应显著高于土曲霉酚。总之，抗体终点滴度值在很大程度上证实了HCV中和数据，一种简化的脂化土曲霉酚变体提供了最高的终点滴度和中和百分比。本研究为土曲霉酚佐剂设计的其他排列奠定了基础，包括在疫苗开发中对其他蛋白质的研究。
