眼科藥物對乙型轉化生長因子誘導蛋白(TGFBIp)多肽之類澱粉纖維形成之影響

Abstract

乙型轉化生長因子誘導蛋白(TGFBIp)是一種廣泛存在於多種組織中的細胞外蛋白質，也是角膜基質層中含量第二高的蛋白質，其突變可引發晶狀角膜失養症(Lattice corneal dystrophy，LCD)和粒狀角膜失養症(Granular corneal dystrophy，GCD)等角膜退行性疾病。然而，目前尚無有效的治療方法來預防、阻止或逆轉因TGFBIp聚集所導致的角膜失養症之進展。由於藥物可能具有交叉作用，治療某種疾病的藥物可能對另一種疾病產生有害或有利的影響，因此在選擇治療患有多重疾病之患者的藥物時需十分謹慎，以避免因藥物的負面作用而導致病情加重。 本研究旨在探討多種常見眼科藥物對TGFBIp多肽片段的類澱粉纖維生成之影響。研究中以TGFBIp第4個FAS1結構域中具有23個氨基酸之長肽片段(TGFBIp611-633)作為體外多肽聚合模型，分析了5種常用眼科藥物成分/小分子—梯莫洛縮蘋酸鹽(Timolol maleate，Tim)、色甘酸鈉(Cromolyn sodium，Crm)、歐弗洒欣(Ofloxacin，Ofx)、新絲菌素硫酸鹽(Neomycin sulfate，Neo)及紅絲菌素(Erythromycin，Ery)——對其纖維化聚集行為的影響。 研究結果顯示，部分原本用於治療其他眼科疾病的藥物，可能具有促進或抑制TGFBIp611-633多肽的纖維化聚集的能力，進而影響LCD的疾病進程。本研究中，我們發現Crm和Ofx對TGFBIp611-633多肽的纖維化聚集無明顯影響；相對的，Tim和Neo則顯示出促進纖維化聚集之效果，而Ery則發現具有抑制聚集的能力。本研究結果不僅可為眼科醫師在為LCD患者選擇適當眼科藥物時提供參考，分析本研究探討的眼藥小分子的不同特性，為未來開發 LCD 的非侵入性藥物治療提供潛在的研究方向與設計指引。

Transforming growth factor β-induced protein (TGFBIp) is a widely expressed extracellular protein and the second most abundant protein in the corneal stroma. Mutations in TGFBIp are associated with corneal degenerative diseases such as lattice corneal dystrophy (LCD) and granular corneal dystrophy (GCD). However, there is currently no effective treatment to prevent, stop, or reverse the progression of TGFBIp aggregation-related corneal dystrophies. Due to potential drug cross-interactions, medications used to treat one condition may inadvertently benefit or aggravate another. Therefore, careful selection is crucial to ensure effective treatment and to prevent adverse effects in patients with multiple diseases. This study aimed to investigate the effects of common ophthalmic drugs on the amyloidogenesis of TGFBIp peptide fragments. An in vitro TGFBIp peptide aggregation system was employed, using a 23-amino acid peptide (TGFBIp611-633) from the fourth FAS1 domain of TGFBIp as a model, to examine the effects of five commonly used ophthalmic drug ingredients/molecules—timolol maleate (Tim), cromolyn sodium (Crm), ofloxacin (Ofx), neomycin sulfate (Neo), and erythromycin (Ery)—on the peptide’s aggregation behavior. The results provide supporting evidence that certain drugs used for some eye diseases may either promote, inhibit or have no effect on the fibrillar aggregation of TGFBIp611-633 peptide. Those that have an effect may potentially influence the progression of LCD by aggravating or alleviating the disease. Specifically, Crm and Ofx showed no significant effect on the fibrillar aggregation of TGFBIp611-633, whereas Tim and Neo exhibited aggregation-promoting effects. In contrast, Ery demonstrated an inhibitory effect on aggregation. These findings offer valuable insights for ophthalmologists in selecting appropriate medications for patients with LCD. Additionally, understanding the distinct properties of the ophthalmic compounds examined in this study may provide some guidance for future development of LCD therapeutics.