Discovery of Small-Molecule Modulators of Protein-RNA Interactions for Treating Cancer and COVID-19

1. Auflage 2023
ISBN: 978-981-19-7813-5
Verlag: Springer Nature Singapore

Buch, Englisch, 128 Seiten, Format (B × H): 160 mm x 241 mm, Gewicht: 442 g

Reihe: Springer Theses

This book describes the development of novel protein–RNA-binding assays and their applications in a high-throughput manner for the identification of small-molecule modulators of protein–RNA interactions to treat cancer and COVID-19.

Modulating protein–RNA interactions with small molecules is expected to provide novel biological insights of the interrelation of diseases with the protein–RNA interactome. The modulations may also be exploited therapeutically. For these reasons, the development of a simple, reliable, and sensitive protein–RNA-binding assay is necessary for high-throughput screening to discover new effective chemical entities capable of acting on diverse protein–RNA interactions. This book discusses the discovery of small-molecule modulators targeting protein–RNA interactions that are potentially valuable to treat cancer and COVID-19 by constructing novel high-throughput screening methods. The results of this dissertation provide valuable insights into the regulation of protein–RNA interactions in chemical biology and drug development.

Zielgruppe

Research

Autoren/Hrsg.

Byun, Wan Gi

Fachgebiete

• Naturwissenschaften Biowissenschaften Angewandte Biologie Biophysik
• Naturwissenschaften Biowissenschaften Biochemie (nichtmedizinisch)
• Naturwissenschaften Physik Angewandte Physik Biophysik
• Naturwissenschaften Biowissenschaften Zellbiologie
• Technische Wissenschaften Verfahrenstechnik | Chemieingenieurwesen | Biotechnologie Verfahrenstechnik, Chemieingenieurwesen

Inhaltsverzeichnis

Chapter 1. Introduction............................................................................ 1

1.1. Protein–RNA interaction.............................................................. 1

1.2. Therapeutic potentials of modulating PRI.................................... 1

1.3. Chemical biology approaches for the discovery of PRI modulator

............................................................................................................. 3

1.4. Aims and scope of the thesis........................................................ 5

1.5. References.................................................................................... 5

Chapter 2. Identification of Small-Molecule Inhibitors of Oncogenic Lin28–Let-7 Interaction           8

2.1. Discovery of a small-molecule inhibitor of protein–microRNA interaction using binding assay with a site-specifically labeled Lin28..................................................................... 8

2.1.1. Introduction..................................................................... 8

2.1.2. Results and discussion................................................... 11

2.1.3. Conclusion..................................................................... 26

2.1.4. Experimental section..................................................... 27

2.1.5. References..................................................................... 37

2.2. Restoring let-7 microRNA biogenesis using a small-molecule inhibitor of the protein–RNA interaction................................................................................................................... 41

2.2.1. Introduction................................................................... 41

2.2.2. Results and discussion................................................... 43

2.2.3. Conclusion..................................................................... 53

2.2.4. Experimental section..................................................... 53

2.2.5. References..................................................................... 58

Chapter 3. Discovery of Small-Molecule Modulators of Protein–RNA Interactions by Fluorescence Intensity-Based Binding Assay............................................................... 61

3.1. Introduction................................................................................ 61

3.2. Results and discussion................................................................ 63

3.3. Conclusion.................................................................................. 76

3.4. Experimental section.................................................................. 76

3.5. References.................................................................................. 85

Chapter 4. Identification of Protein–RNA Interaction Modulators for Treating COVID-19   88

4.1. Harnessing stress granule formation by small molecules to inhibit the cellular replication of SARS-CoV-2......................................................................................................... 88

4.1.1. Introduction................................................................... 88

4.1.2. Results and discussion................................................... 89

4.1.3. Conclusion................................................................... 103

4.1.4. Experimental section................................................... 104

4.1.5. References.................................................................... 110

4.2. Discovery of a small-molecule degrader of SARS-CoV-2 Nsp1 by autophagic pathway  112

4.2.1. Introduction.................................................................. 112

4.2.2. Results and discussion................................................. 113

4.2.3. Conclusion................................................................... 119

4.2.4. Experimental section................................................... 119

4.2.5. References 121

Über Autor(innen)

Wan Gi Byun received his B.S. degree in Department of Chemistry at Seoul National University, Korea in 2015. In the same year, he joined Prof. Seung Bum Park’s group in the Department of Chemistry at the Seoul National University and started to study chemical biology and drug discovery. His research during Ph.D. involved the development of high-throughput screening systems and identification of small-molecule modulators of protein–RNA interactions to overcome human diseases including cancer and COVID-19. After he got his Ph.D. degree in 2022, he is currently a post-doctoral researcher in Department of Chemistry, Seoul National University. His current research focus on the development of broadspectrum, pan-coronavirus antiviral drugs.