Material Type  

 학위논문

 

0017162563

Date and Time of Latest Transaction  

20250211152027

ISBN  

9798384015178

DDC  

540

Author  

Kissai, Mildred Apollo.

Title/Author  

I. Chemical Biology Tools to Modulate the Innate Immune System: Cyclic GMP-AMP Synthase Inhibitors and Phase Separation Modulators II. Structural Studies of Vimentin-Binding Small Molecules.

Publish Info  

[S.l.] : The Scripps Research Institute., 2024

Publish Info  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Material Info  

170 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-02, Section: B.

General Note  

Advisor: Lairson, Luke L.

학위논문주기  

Thesis (Ph.D.)--The Scripps Research Institute, 2024.

Abstracts/Etc  

요약The cGAS-STING pathway is an important innate immune system pathway that recognizes the double-stranded DNA of pathogens like bacteria, viruses, and aberrantly processed DNA in the cytosol. Its dysregulation has implications in cancer and several autoimmune disorders. For instance, a type 1 interferonopathy called Aicardi-Goutieres Syndrome is a result of an over-active cGAS-STING pathway due to a loss-of-function mutation in a prominent endonuclease TREX1. Animal models of systemic autoinflammation (TREX1 knockout mice) have been rescued by selective knockout of cGAS or STING. This shows that inhibiting the cGAS-STING pathway can be targeted to develop treatments for type 1 interferonopathies. Consequently, a natural product screen using the human monocytic cell line THP1 resulted in the discovery of several cGAS-STING pathway inhibitors. Through careful molecular and structural studies, these inhibitors were characterized to reveal their molecular target and binding site. Cladophorol A, a novel inhibitor for the ATP-binding site on cGAS was discovered and characterized, revealing that natural products can offer a chemically diverse source of cGAS-STING pathway inhibitors, and potentially, therapies for type 1 interferonopathies.Additionally, the cGAS-STING pathway plays a crucial role in the innate immune response through the recognition of cytosolic dsDNA by cGAS. Upon binding to dsDNA, cGAS undergoes a conformational change and phase separates into distinct liquid-liquid phase separated condensates. These condensates enable the rapid activation of biochemical reactions necessary for immune signaling. Small molecules that modulate these condensates, termed condensate-modifying drugs, have emerged as potential therapeutic agents. Chapter 3 focuses on designing phenotypic screens for the discovery and characterization of small molecules that dissolve cGAS-DNA condensates, potentially offering novel treatments for inflammatory diseases like type I interferonopathies. Using a combination of in vitro assays and cell-based screens, we successfully developed assays for screening condensate dissolvers. This research highlights the therapeutic potential of targeting condensates in the cGAS-STING pathway and lays the groundwork for future drug discovery efforts in this area.On another note, cancer metastasis remains a significant challenge in chemotherapy due to the presence of cancer stem cells (CSCs), which exhibit enhanced migratory capabilities and metastatic potential through the epithelial-mesenchymal transition. Previous research identified a novel small molecule, FiVe1, which selectively targets mesenchymal cancer cells-a CSC subtype-by binding to the intermediate filament protein vimentin. Although initial hydrogen-deuterium exchange mass spectrometry studies did not pinpoint FiVe1's binding site, azidation proteomics and limited proteolysis mass spectrometry confirmed that FiVe1 interacts with vimentin residues 268-282. Subsequent in silico docking and planned mutational studies will further elucidate FiVe1's mechanism. Structural and solubility challenges notwithstanding, FiVe1 offers a promising avenue for targeting metastatic CSCs and adding to chemical biology tools that may enhance therapeutic outcomes in cancer treatment.

Subject Added Entry-Topical Term  

Chemistry.

Subject Added Entry-Topical Term  

Biophysics.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Oncology.

Subject Added Entry-Topical Term  

Immunology.

Index Term-Uncontrolled  

DNA sensor

Index Term-Uncontrolled  

Innate immune system

Index Term-Uncontrolled  

Vimentin

Index Term-Uncontrolled  

Cancer stem cells

Index Term-Uncontrolled  

Aicardi-Goutieres Syndrome

Added Entry-Corporate Name  

The Scripps Research Institute Chemical Biology

Host Item Entry  

Dissertations Abstracts International. 86-02B.

Electronic Location and Access  

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Control Number  

joongbu:658275