Construction of chemical library including flavonoids and peptides with potential biological activity

다국어 초록 (Multilingual Abstract)

Part I. Design, Synthesis, and Biological Evaluation of Flavonoids
Abstract
Type 2 diabetes mellitus (T2DM) remains a major metabolic disorder, prompting extensive research to identify new therapeutic targets. Among these, the G-protein-coupled receptor GPR120 has gained attention due to its involvement in metabolic regulation and potential as a therapeutic target for T2DM. This study investigates the potential of Lysionotin, a naturally occurring flavonoid, as a candidate GPR120 agonist. Based on structural similarities between Lysionotin and known GPR120 ligands, I synthesized a series of flavonoid-based compounds. The compounds were classified into two primary categories, flavones and isoflavones, based on the position of the phenyl group attached to either the C-2 or C-3 position of the chromone structure. Additional structural modifications were introduced at the C-5 and C-7 positions to optimize functional activity. These compounds were then subjected to biological assays to evaluate their efficacy as GPR120 agonists. Our findings suggest that these newly designed flavonoid analogs have promising potential as therapeutic agents for metabolic disorders, including T2DM, through selective targeting of GPR120.
Keywords : Type 2 Diabetes Mellitus (T2DM), GPR120 agonist, Flavonoid, Medicinal Chemistry, Molecular Docking

Part II. Peptide Library Synthesis
Abstract
In this study, peptide-based combinatorial libraries were designed and synthesized using two complementary screening platforms: One-Bead-One-Compound (OBOC) and DNA-Encoded Library (DEL) technologies. To enhance molecular diversity and functional performance, unnatural amino acids—including adenine-based and phosphonic acid–containing residues—were strategically incorporated into the peptide sequences. OBOC peptide libraries were constructed using the split-and-mix solid-phase synthesis method on resin beads, with carefully designed peptide scaffolds featuring unnatural amino acids at defined positions. Fluorescence-based high-throughput screening was performed using labeled proteins, and beads exhibiting strong fluorescence signals were selectively sorted using flow cytometry. These selected candidates were proposed for further analysis, including sequence identification and structure–activity relationship (SAR) studies. In parallel, a DEL platform was employed by stepwise coupling of amino acids and their corresponding DNA tags, enabling the generation of peptide libraries with precisely encoded sequences. After screening, selected beads were subjected to PCR amplification and DNA purification. While amplification and DNA fragment detection were successful, downstream DNA sequencing was hindered, likely due to DNA damage during peptide synthesis.
This work highlights the potential of OBOC and DEL strategies for the discovery of specific peptide ligands. It also underscores the importance of optimizing chemical conditions to preserve molecular integrity during synthesis—particularly in DNA-encoded systems—to ensure analytical compatibility and screening efficiency.
Key Words : Peptide Library OBOC (One-Bead-One-Compound) DEL (DNA-Encoded Library) Unnatural Amino Acids High-throughput Screening

목차 (Table of Contents)

• Part I. Design, Synthesis, and Biological Evaluation of Flavonoids 1
• Abstract 1
• Comprehensive Introduction 2
• 1. Significance of Flavonoids in Human Health 2
• 2. Targeting GPR120: Therapeutic Relevance and Emerging Strategies 4
• 3. Type 2 Diabetes Mellitus and the Role of GPR120 Agonists 5
• Part I-1. Design, Synthesis and Biological Evaluation of Lysionotin Derivatives 8
• Chapter 1. Introduction 8
• Chapter 2. Results and Discussion 10
• 2.1. Design of Lysionotin Derivatives as GPR120 Ligands 10
• 2.2. Chemistry 14
• 2.2.1. Synthesis of Lysionotin Derivatives 14
• 2.3. Biological Evaluation of Lysionotin Derivatives 19
• Chapter 3. Conclusion 22
• Part I-2. Flavonoid Derivatives Synthesis 24
• Chapter 1. Introduction 24
• Chapter 2. Results and Discussion 26
• 2.1. Design of Flavonoid Derivatives 26
• 2.2. Chemistry 28
• 2.3. Biological Evaluation of GPR120 Activity of Flavonoid Isomers 34
• Chapter 3. Conclusion 39
• Materials and Methods : Part I. Flavonoids Synthesis 41
• Part II. Peptide Library Synthesis 69
• Abstract 69
• Comprehensive Introduction 71
• 1. Advantages of Peptide-Based Drug Development and the Application of Unnatural Amino Acids 71
• Part II-1. Construction of OBOC Peptide Library 73
• Chapter 1. Introduction 73
• 1.1. OBOC Peptide Libraries as a Versatile Platform for Ligand Discovery and Therapeutic Development 73
• Chapter 2. Results and Discussion 75
• 2.1. Synthesis of Adenine Moiety Unnatural Amino Acids 75
• 2.2. OBOC Peptide Library Construction 81
• 2.2.1. OBOC Library Construction Using Adenine Moiety Unnatural Amino Acids 81
• 2.2.2. OBOC Library Construction Containing PTP1B inhibitor moiety 84
• 2.3. Biological Evaluation of OBOC Peptide Library via High-Throughput Screening 93
• Chapter 3. Conclusion 93
• Part II-2. DNA Encoded Peptide Library Construction 106
• Chapter 1. Introduction 106
• 1.1. DNA-Encoded Peptide Libraries for Targeted Ligand Discovery 106
• Chapter 2. Results & Discussion 109
• 2.1. Construction of DNA Encoded Peptide Library 111
• 2.2. Biological Evaluation of DEL Peptide Library via High-Throughput Screening 116
• Chapter 3. Conclusion 119
• Materials and Methods : Part II 120
• References 141
• Appendix 152
• 논문요약 202