配體和受體之間的識別在新藥發現和新藥傳遞策略中具有重要作用。眾所周知，蛋白藥物在體內循環過程中不穩定，並且其細胞攝取效率通常不理想。因此，通過細胞表面特定受體增強蛋白質進入靶細胞的滲透性，已成為現代配體-受體介導的傳遞裡一個重大的挑戰。
以醣為基礎的配體，如甘露糖-6-磷酸（M6P）和甘露糖及其相應的受體，包括M6P受體和甘露糖受體，被認為是重要的傳遞系統。然而，儘管這些糖基配體的多價性及其在蛋白質表面的位置或數量很重要，但這些化學材料（包括配體、多價配體及其在蛋白質表面的生物接合）的有效製備尚未被廣泛研究。
在本文中，主要關注的是甘露糖相關配體和多價配體的設計與合成。經過我們系統地製備不同的多價配體，這些配體在蛋白質的表面進行生物架接。這些複合物被應用於細胞實驗，包括攝取效率評估。酶替代療法（ERT）對於溶酶體貯積病（LSDs）的一個現有限制是由於蛋白質藥物上的M6P配體含量低，酶進入細胞的效率不高。作為概念驗證，我們利用含有α-甘露苷酶基糖蛋白和合成配體的各種複合物作為我們的模型系統，針對細胞性α-甘露苷症（AM）研究，這是一種目前了解較少的溶酶體貯積病（LSDs）。令人欣喜的是，這種化學架接方法能夠改善酶進入細胞的攝取。
在另一方面，溶酶體靶向嵌合體（LYTACs）通過將膜蛋白引導到溶酶體中進行降解，代表了一種主要方法。在本研究中，我們計劃利用甘露糖受體傳遞系統來擴展這一策略，這一系統尚未被完全研究。為了達到我們的目標，我們進行了設計和合成多價甘露糖配體的模型研究。
在最後一部分，通過類似的化學架接策略，將細胞穿透肽（CPPs）和螢光分子應用於蛋白藥物的接合，這使我們能夠研究蛋白藥物是否可以直接穿過血腦屏障（BBB）或通過鼻腔給藥來繞過它進入大腦。

The recognition between ligands and receptors plays an important role in new drug discovery and new drug delivery strategy.
As we know, protein drugs are unstable during circulation, and their cellular uptake efficiency is often unsatisfactory. Therefore, enhancing the penetration of proteins into targeted cells through specific receptors on the cell surface has become a significant scientific challenge in modern ligand-receptor mediated delivery.
Sugar-based ligands such as mannose-6-phosphate (M6P) and mannose as well as their corresponding receptors including M6P receptor and mannose receptor, respectively are considered important delivery systems. However, although their multivalence and the locations or numbers of sugar-based ligands on the protein surface are important, the efficient preparation of these chemical materials, including ligands, multivalent ligands, and their bio-conjugation on protein surface, has not been extensively investigated yet.
In this thesis, the main focus is on the design and synthesis of mannose-related ligands and multivalent ligands. After our systematic preparation of ligands with various multivalence, the bio-conjugation of these ligands on protein surface was performed and characterized. These adducts were applied for cell-based studies including uptake efficiency evaluations.
One of current limitations of enzyme replacement therapy (ERT) for lysosomal storage diseases (LSDs) is the inefficient uptake of enzymes into cells due to low abundance of M6P ligands on protein drugs. For a proof of concept, we utilized these various adducts containing alpha-mannosidase-based glycoproteins and synthetic ligands as our model systems toward the cellular alpha-mannosidosis (AM) study, one of LSDs but less understanding. To our delight, this chemical conjugation approach enables to improve enzyme uptake into cells.
On the other hand, lysosome-targeting chimeras (LYTACs) represent a primary method for degrading membrane proteins by directing them into lysosomes. In this study, we plan to extend this strategy by using the mannose receptor delivery system, which has not been completely investigated. To reach our goal, we did model studies for designing and synthesizing multivalent mannose ligands for this purpose.
In the last part, following the similar chemical conjugation strategy, cell-penetrating peptides (CPPs) and fluorophores were applied to conjugate on protein drugs, which allows us to study whether protein drugs can directly cross the blood-brain barrier (BBB) or bypass it via nasal delivery to access the brain.

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