肽聚醣 (peptidoglycan, PGN) 乃是組成細菌細胞壁的主要元件，經由酵素作用
產生的肽聚醣的片段能誘發先天性免疫反應，促進細胞激素的生成以對抗外來的微
生物。然而，許多病原體會利用其肽聚醣的再修飾進而影響其和宿主免疫系統的作
用。因此，為了能夠完整地了解肽聚醣如何誘發先天性免疫系統，我們需要得到結
構各異之肽聚醣碎片。除此之外，抗生素的濫用導致了日趨嚴重的細菌抗藥性問題。
研究顯示，阻斷細菌細胞壁的生成可有效的達到殺菌的效果。其中，生成細菌細胞
壁的必須酵素，轉醣酶 (transglycosylase, TGase) 就是一個很好的標靶酵素。尋找出有效的TGase 抑制劑，是目前解決抗藥性的方法之一。因此，本論文分為以下兩部分探討：
第一部分：氮取代肽聚醣之合成方法與其對免疫反應之關聯性
本實驗室發展了合成氮取代肽聚醣片段之方法。首先，我們備置了正交氮保護
基之雙糖建構組元 (building block)。為了合成更長的肽聚醣片段，我們利用RRV
(relative reactivity value) 方法將此雙糖組成四糖建構組元。有了這些建構組元後，經由保護基的轉換、氧的烷基化、連接胜肽鏈、去除所有的保護基後，即可得到不同氮取代之肽聚醣片段。藉此，即可進一步研究其和PGN 識別受體NOD2 產生免疫反應的關聯性。
第二部分：開發轉醣酶之偏極化螢光測定法並篩選具抑制效果之分子
此部份，我們合成了含有螢光基團之轉醣酶抑制劑F-epi-lipid II (2)。此螢光探
針可應用在偏極化螢光測定法 (fluorescence polarization assay, FP assay)，並且和作用在予體位(donor site)的抑制劑富樂黴素 (Moenomycin A, Moe A)搭配應用。由實驗結果得知，F-epi-lipid II 作用於鮑氏不動桿菌轉醣酶 (A. baumannii PBP1b)的受體位 (acceptor site)。藉由此測定法，我們篩選了含有1500 個分子的分子庫，包含了實驗室發展的C-linked lipid II 衍生物。結果顯示兩個天然物有較佳的抑制活性以及搭配安比西林(ampicillin) 對抗藥性金黃色葡萄球菌(MRSA) 有較佳的抑制效果。

Peptidoglycan (PGN) is an essential component of bacterial cell wall and PGN fragments are discovered to initiate innate immune responses and stimulate the production of a wide range of cytokines against invading microorganisms. Interestingly, many pathogenic species contain secondary glycan strand modifications affecting their
interaction with elements of the immune system. For detail investigating the peptidoglycan-induced innate immunity, structurally diverse PGN fragments are required.
Besides, the overuse of antibiotics has led to increasing bacterial resistance. Scientists are engaged in finding new antibiotics. By long term research, interrupting the biosynthetic
steps of bacterial cell wall causes the death of bacteria, and transglycosylase (TGase), an essential enzyme for cell wall biosynthesis, is recognized as a promising target. The
discovery of new TGase inhibitors is one of the efficient strategies to overcome resistance. Herein, the thesis is divided into two parts:
The topic title of the first chapter is “Diverse synthesis of bacterial N-substituted muropeptides and disaccharide dipeptides (GMDPs) for human NOD2 stimulation”. In this part, we developed a flexible synthetic approach to prepare N-substituted PGN
fragments. First, orthogonally N-protected disaccharide building blocks were synthesized to lead for preparing a longer glycan backbone. Notably, the tetrasaccharide chain was
successfully constructed by using the RRV (relative reactivity value) strategy. With the qualified disaccharide building blocks in hand, diverse N-substituted muropeptides were prepared through a sequence of steps, including transformations of the protecting groups, O-alkylation, peptide conjugation, and deprotection. These valuable compounds were applied for the human NOD2 stimulation studies. Next, the topic title of the second part is “Development of a fluorescence polarization assay for the acceptor-site on TGase.” In this part, the fluorescence-labeled TGase inhibitor, F-epi-lipid II (2), was developed as a chemical probe in the fluorescent polarization assay platform toward TGase. Based on our FP assay
results, F-epi-lipid II (2) was identified as the acceptor site binder against A. baumannii PBP1b. Next, a 1500-membraned small molecule library, including our synthetic C-linked lipid II analogues were applied for screening. Interestingly, two natural
compounds with low IC50 values were identified, and both showed a synergistic effect with ampicillin against MRSA. The newly formed C-linked lipid II analogue in this study was validated to locate at the acceptor site of TGase and showed better inhibition than our
previously synthesized one by using FP and HPLC assay.

摘要......................................................... i
Abstract .................................................. iii
謝誌 ........................................................ v
Table of contents .......................................... vi
List of Figures ............................................ ix
List of Schemes ............................................ xi
List of Tables ............................................ xii
Glossary of Abbreviations ................................ xiii
Part I: Diverse synthesis of bacterial N-substituted muropeptides and disaccharide dipeptides (GMDPs) for human NOD2 stimulation.................................................. 1
1. Introduction ............................................. 2
1.1 Bacterial cell wall–Peptidoglycan (PGN)........................................................ 3
1.2 Modification of PGN glycan chain ........................ 4
1.2.1 N-Deacetylated peptidoglycan........................... 4
1.2.2 O-Acetylated NAM....................................... 4
1.2.3 N-Glycolylation of NAM ................................ 5
1.2.4 Other post-modifications of the glycan chain............6
1.3 Current investigation on the preparation of PGN fragments ............................................................. 6
1.4 Host recognition of muropeptides ....................... 10
1.4.1 Dissection of the molecular basis of muropeptides that recognize hNOD2............................................. 11
1.5 Motivation ............................................. 13
2. Results and Discussion .................................. 14
2.1 Synthesis of monosaccharide building blocks............. 15
2.2 Parallel synthesis of disaccharide building blocks.......17
2.3 Model studies: selective removal of orthogonal P1 and P2 ............................................................ 18
2.4 Modular synthesis of PGN tetrasaccharide backbones ............................................................ 20
2.5 Diverse synthesis of N-substituted GMDPs................ 23
2.6. The hNOD2 assay evaluation ............................ 27
3. Conclusion .............................................. 28
References ................................................. 30

Part II: Development of a fluorescence polarization assay for the acceptor-site on TGase...................................34
1. Introduction .............................................35
1.1 Bacterial cell wall biosynthesis.........................36
1.2 Bacterial TGase is a promising target....................37
1.3 Current discovery of TGase inhibitors ...................38
1.4 Motivation ..............................................39
2. Results and discussion....................................42
2.1 Synthesis of F-epi-lipid II (2) as a fluorescent probe...43
2.2 Synthesis of epi-lipid II-C-O-PP-C20 (18) as a C-linked inhibitor ...................................................44
2.3 Development of fluorescence polarization assay for HTS...45
2.3.1 The effect of detergent and the selection of appropriate TGase........................................................45
2.3.2 The binding influence between TGase and epi-lipid II analogues ...................................................46
2.3.3 Review of the fluorescent probes: the effect of lipid length.......................................................47
2.3.4 Working concentration of fluorescent probe for HTS.....48
2.4 Binding site validation: Competitive evaluation of site- occupied probe and the complement inhibitor..................49
2.5 Hits screening by the validated acceptor site FP assay...51
2.6 biological evaluation of screened hits ..................52
3. Conclusion ...............................................55
References ..................................................56
Experimental section ........................................59
Appendix: NMR spectra ......................................120
Appendix: Publication ......................................164

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