PDF(Pubmed)
Abstract：
Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037\'s in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.
摘要：
接种疫苗可以帮助预防感染，也可以用于治疗癌症，过敏,甚至可能药物过量。佐剂增强疫苗反应，但是目前，他们进步和发展的道路是渐进的。我们使用THP-1细胞进行表型小分子筛选，以鉴定核因子-κB（NF-κB）激活分子，然后使用原代人外周血单核细胞进行定量肿瘤坏死因子免疫测定，对前导靶文库进行反筛选。对原代细胞进行筛选，鉴定出一种咪唑并嘧啶，被称为PVP-037。此外，而PVP-037没有明显激活THP-1细胞，它表现出广泛的先天免疫激活，包括体外原代人白细胞的NF-κB和细胞因子诱导以及小鼠中流感和SARS-CoV-2抗原特异性体液反应的增强。几种从头合成的结构增强迭代提高了PVP-037的体外功效，效力，效力物种特异性活动，和体内佐剂。总的来说,我们鉴定了咪唑并嘧啶Toll样受体-7/8佐剂,其与水包油乳剂协同作用以增强免疫应答.
