Abstract：
ERAP1 is an emerging target for a large subclass of severe autoimmune diseases known as \"MHC-I-opathy\", together with tumor immunity. Nevertheless, effective inhibitors targeting ERAP1 remain a challenge. In this study, a novel food-derived natural product ERAP1-targeting inhibitor, carnosic acid, was identified, and to our knowledge, it is one of the best active compounds among the highly selective inhibitors targeting the orthosteric site of ERAP1. The results reveal that carnosic acid could bind strongly, like a key to the ERAP1 active site in the biased S1\' pocket, which is different from the binding mode of the existing orthosteric site inhibitors. HLA-B27-mediated cell modeling validated that carnosic acid has the activity to reverse the AS-associated cellular phenotype brought on by ERAP1 through inhibition. Our findings provide insights into the design of potent inhibitors against the ERAP1 orthosteric site and the discovery of a key direct target of carnosic acid.
摘要：
ERAP1是称为“MHC-I病”的严重自身免疫性疾病的一大亚类的新兴靶标，与肿瘤免疫一起。然而，靶向ERAP1的有效抑制剂仍然是一个挑战。在这项研究中,一种新型的食品衍生天然产物ERAP1靶向抑制剂，鼠尾草酸,被确认,根据我们的知识，它是靶向ERAP1正构位点的高选择性抑制剂中最好的活性化合物之一。结果表明，鼠尾草酸可以强烈结合，就像偏置S1口袋中ERAP1活性位点的钥匙，这不同于现有的正构位点抑制剂的结合模式。HLA-B27介导的细胞建模验证了鼠尾草酸具有通过抑制逆转由ERAP1引起的AS相关细胞表型的活性。我们的发现为针对ERAP1正构位点的有效抑制剂的设计以及鼠尾草酸的关键直接靶标的发现提供了见解。
