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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
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
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152027
- ISBN
- 9798384015178
- DDC
- 540
- 서명/저자
- 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
- 발행사항
- [Sl] : The Scripps Research Institute, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 170 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
- 주기사항
- Advisor: Lairson, Luke L.
- 학위논문주기
- Thesis (Ph.D.)--The Scripps Research Institute, 2024.
- 초록/해제
- 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.
- 일반주제명
- Chemistry
- 일반주제명
- Biophysics
- 일반주제명
- Biochemistry
- 일반주제명
- Oncology
- 일반주제명
- Immunology
- 키워드
- DNA sensor
- 키워드
- Vimentin
- 기타저자
- The Scripps Research Institute Chemical Biology
- 기본자료저록
- Dissertations Abstracts International. 86-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798384015178
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■0820 ▼a540
■1001 ▼aKissai, Mildred Apollo.
■24510▼aI. 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
■260 ▼a[Sl]▼bThe Scripps Research Institute▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a170 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-02, Section: B.
■500 ▼aAdvisor: Lairson, Luke L.
■5021 ▼aThesis (Ph.D.)--The Scripps Research Institute, 2024.
■520 ▼aThe 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.
■590 ▼aSchool code: 1179.
■650 4▼aChemistry
■650 4▼aBiophysics
■650 4▼aBiochemistry
■650 4▼aOncology
■650 4▼aImmunology
■653 ▼aDNA sensor
■653 ▼aInnate immune system
■653 ▼aVimentin
■653 ▼aCancer stem cells
■653 ▼aAicardi-Goutieres Syndrome
■690 ▼a0485
■690 ▼a0786
■690 ▼a0487
■690 ▼a0992
■690 ▼a0982
■71020▼aThe Scripps Research Institute▼bChemical Biology.
■7730 ▼tDissertations Abstracts International▼g86-02B.
■790 ▼a1179
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17162563▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
