杜玲嫻Tu, Ling-Hsien張庭豪Zhang, Ting-Hao2023-12-082023-07-132023-12-082023https://etds.lib.ntnu.edu.tw/thesis/detail/1a44b971d88abc2ba7c45f0b83d57c0a/http://rportal.lib.ntnu.edu.tw/handle/20.500.12235/120976胜肽的不可逆聚集現象嚴重限制了其作為藥物的生物利用度和治療活性，因此有效抑制胜肽聚集是一個重要的挑戰。人類降鈣素（Human calcitonin, hCT）是一種32個胺基酸組成的胜肽激素，由甲狀腺（Thyroid gland）中的濾泡旁細胞（Parafollicular cells）分泌，具有調節血鈣水平和維持骨骼結構的生理功能，因此在治療骨骼相關疾病，如骨質疏鬆症和佩吉特氏症(Paget's Disease)，方面具有潛在價值。然而，hCT具有高度聚集的傾向，容易形成類澱粉蛋白纖維（Amyloid fibril），這可能降低其原有功能並限制其作為藥物的應用潛力。目前臨床上，鮭魚降鈣素鮭魚降鈣素（Salmon calcitonin, sCT）因其較高的生物活性和極低的聚集傾向而取代了hCT成為廣泛使用的胜肽藥物，但由於sCT與hCT之間的序列相似性較低，患者在使用後可能產生嚴重的副作用和免疫反應，因此尋找有效抑制hCT聚集並保持其治療活性的方法便十分重要。 在本實驗中，我們透過一系列實驗，加入不同滲透物小分子，並利用不同濃度去觀察其對於hCT生成類澱粉蛋白纖維的影響，最後發現了具有葡萄糖分子的糖類滲透物對於hCT生成類澱粉蛋白纖維是具有延緩效果的。透過這些實驗結果，我們期望能尋求可用來穩定hCT的藥物添加物，並有助於設計對抗類澱粉蛋白變性疾病（Amyloidosis）之藥品。The irreversible aggregation of peptides severely limits their bioavailability and therapeutic efficacy as drugs, making the effective inhibition of peptide aggregation a critical challenge. Human calcitonin (hCT), a peptide hormone composed of 32 amino acids,is secreted by parafollicular cells in the thyroid gland. It plays a vital role in regulating blood calcium levels and maintaining skeletal integrity, making it a potential candidate for the treatment of bone-related disorders such as osteoporosis and Paget's disease. However, hCT exhibits a high propensity for forming amyloid fibrils through aggregation, which can diminish its native functionality and hinder its therapeutic potential as a drug. Currently, salmon calcitonin (sCT) has been widely used as a peptide drug due to its higher bioactivity and significantly lower aggregation tendency compared to hCT. Unfortunately, the low sequence homology between sCT and hCT results in severe side effects and immune reactions in patients. Therefore, thedevelopment of effective strategies to inhibit hCT aggregation while preserving its therapeutic activity is of paramount importance.In this experiment, we conducted a series of experiments by introducing different small molecule osmolytes and observing their effects on the formation of amyloid fibrils by hCT at various concentrations. Ultimately, we discovered that a simple glucose-based sugar osmolyte exhibited inhibitory effects on the generation of amyloid fibrils by hCT. Based on these experimental results, we aim to identify pharmaceutical additives that can stabilize hCT and contribute to the design of drugs against amyloidosis, a group of disorders characterized by the deposition of amyloid fibrils.人類降鈣素錯誤摺疊聚集類澱粉蛋白纖維糖類滲透物human calcitoninmisfoldingaggregationamyloid fibrilssugar osmolytesetd