Okuno Daisuke, Sakamoto Noriho, Hayashi Hideki, Fukuda Tsutomu, Akiyama Yoshiko, Iketani Chiaki, Murakami Ritsuko, Tokito Takatomo, Miyamura Takuto, Yura Hirokazu, Kido Takashi, Ishimoto Hiroshi, Takemoto Shinnosuke, Takazono Takahiro, Nishino Tomoya, Ishimatsu Yuji, Ishihara Jun, Takeda Kohsuke, Tanaka Yoshimasa, Mukae Hiroshi
Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.
ChemMedChem. 2025 May 5;20(9):e202401001. doi: 10.1002/cmdc.202401001. Epub 2025 Feb 10.
Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic interstitial lung disease characterized by irreversible loss of lung function and a poor prognosis. Type I collagen, a major component of the extracellular matrix, plays a central role in the pathogenesis of fibrosis and is considered a key molecular target for therapeutic intervention. While current anti-fibrotic therapies demonstrate limited efficacy in slowing disease progression, their clinical impact remains suboptimal due to poor pharmacokinetic properties and non-curative therapy. Moreover, the development of effective anti-fibrotic agents targeting collagen synthesis is hindered by the absence of robust, cost-effective, high-throughput drug screening platforms. In this study, we established a novel screening system designed to identify small molecules that inhibit the expression of the COL1A2 gene, which encodes type I collagen. Utilizing this system, we screened a library of natural and synthetic compounds developed at Nagasaki University and identified lamellarin D as a potent inhibitor of COL1A2 expression and subsequent type I collagen production. These findings suggest that lamellarin D, through its unique molecular mechanism, may serve as the foundation for the development of a new class of IPF treatments aimed at targeting the underlying fibrotic processes.
特发性肺纤维化(IPF)是一种进行性慢性间质性肺疾病,其特征为肺功能不可逆转丧失且预后不良。I型胶原蛋白是细胞外基质的主要成分,在纤维化发病机制中起核心作用,被认为是治疗干预的关键分子靶点。尽管目前的抗纤维化疗法在减缓疾病进展方面疗效有限,但由于药代动力学特性不佳和非治愈性治疗,其临床影响仍不尽人意。此外,由于缺乏强大、经济高效的高通量药物筛选平台,阻碍了针对胶原蛋白合成的有效抗纤维化药物的开发。在本研究中,我们建立了一种新型筛选系统,旨在鉴定抑制编码I型胶原蛋白的COL1A2基因表达的小分子。利用该系统,我们筛选了长崎大学开发的天然和合成化合物库,并确定海兔毒素D是COL1A2表达及随后I型胶原蛋白产生的有效抑制剂。这些发现表明,海兔毒素D通过其独特的分子机制,可能为开发一类针对潜在纤维化过程的新型IPF治疗方法奠定基础。