Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J Nutr Biochem. 2023 Jan;111:109178. doi: 10.1016/j.jnutbio.2022.109178. Epub 2022 Oct 11.
Dysregulated production of peptide hormones is the key pathogenic factor of various endocrine diseases. Endoplasmic reticulum (ER) associated degradation (ERAD) is a critical machinery in maintaining ER proteostasis in mammalian cells by degrading misfolded proteins. Dysfunction of ERAD leads to maturation defect of many peptide hormones, such as provasopressin (proAVP), which results in the occurrence of Central Diabetes Insipidus. However, drugs targeting ERAD to regulate the production of peptide hormones are very limited. Herbal products provide not only nutritional sources, but also alternative therapeutics for chronic diseases. Virtual screening provides an effective and high-throughput strategy for identifying protein structure-based interacting compounds extracted from a variety of dietary or herbal sources, which could be served as (pro)drugs for preventing or treating endocrine diseases. Here, we performed a virtual screening by directly targeting SEL1L of the most conserved SEL1L-HRD1 ERAD machinery. Further, we analyzed 58 top-ranked compounds and demonstrated that Cryptochlorogenic acid (CCA) showed strong affinity with the binding pocket of SEL1L with HRD1. Through structure-based docking, protein expression assays, and FACS analysis, we revealed that CCA enhanced ERAD activity and promoted the degradation of misfolded proAVP, thus facilitated the secretion of well-folded proAVP. These results provide us with insights into drug discovery strategies targeting ER protein homeostasis, as well as candidate compounds for treating hormone-related diseases.
肽激素分泌失调是各种内分泌疾病的关键致病因素。内质网（ER）相关降解（ERAD）是哺乳动物细胞中维持 ER 蛋白稳态的关键机制，通过降解错误折叠的蛋白质。ERAD 功能障碍导致许多肽激素的成熟缺陷，如加压素原（proAVP），导致中枢性尿崩症的发生。然而，靶向 ERAD 调节肽激素产生的药物非常有限。草药产品不仅提供营养来源，还为慢性疾病提供替代疗法。虚拟筛选为从各种饮食或草药来源中提取的基于蛋白质结构的相互作用化合物提供了一种有效且高通量的识别策略，这些化合物可以作为（前）药物，用于预防或治疗内分泌疾病。在这里，我们通过直接针对最保守的 SEL1L-HRD1 ERAD 机制中的 SEL1L 进行了虚拟筛选。此外，我们分析了 58 种排名靠前的化合物，证明 Cryptochlorogenic acid (CCA) 与 SEL1L 与 HRD1 的结合口袋具有很强的亲和力。通过基于结构的对接、蛋白质表达测定和 FACS 分析，我们揭示了 CCA 增强了 ERAD 活性，促进了错误折叠的 proAVP 的降解，从而促进了折叠良好的 proAVP 的分泌。这些结果为我们提供了针对 ER 蛋白稳态的药物发现策略的深入了解，以及治疗激素相关疾病的候选化合物。
