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Multi-Omics and High-Content Screening for the Discovery of Plant Cyclic Peptides in Cancer Drug Development
Multi-Omics and High-Content Screening for the Discovery of Plant Cyclic Peptides in Cancer Drug Development
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202105239
- ISBN
- 9798291568620
- DDC
- 616.99
- 저자명
- Shafiq, Khadija.
- 서명/저자
- Multi-Omics and High-Content Screening for the Discovery of Plant Cyclic Peptides in Cancer Drug Development
- 발행사항
- [Sl] : University of Michigan, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 219 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 주기사항
- Advisor: Kersten, Roland D.;Sexton, Jonathan Z.
- 학위논문주기
- Thesis (Ph.D.)--University of Michigan, 2025.
- 초록/해제
- 요약Over the past century, nearly half of the FDA-approved drugs were sourced from natural products, with plants representing a prolific reservoir of chemotherapeutics. Among these, cyclic peptides have emerged as promising scaffolds for cancer drug discovery, offering the metabolic stability and target specificity of biologics alongside the oral bioavailability and membrane permeability of small molecules. Despite their promise, plant natural product drug discovery has been deprioritized by the pharmaceutical industry due to three persistent bottlenecks: (1) low-yield isolation from source plant material, (2) chemical rediscovery in bioactivity-guided fractionation, and (3) synthetic barriers to macrocyclic complexity and lead diversification. This dissertation addresses these challenges through an integrated multi-omics strategy that combines metabolomics, genome mining, proteomics, and metabolic engineering to identify novel cyclic peptides from plant sequencing data. Additionally, a high-content screening (HCS) platform was developed to evaluate the cytotoxicity profiles of these peptides in cell-based cancer models. The integrated multi-omics and HCS approach led to the discovery of cyclic peptides from three distinct classes of ribosomally synthesized and post-translationally modified peptides (RiPPs): a cyclopeptide alkaloid, multiple stephanotic acid peptides, and two cysteine-rich peptides. These peptides, collectively termed burpitides, are cyclized by copper-dependent BURP-domain-containing proteins (burpitide cyclases) encoded within the same precursor gene as their peptide substrates. This genomic architecture enables discovery via sequence-based mining of plant genomes and transcriptomes. Proteome database search tools facilitated the detection of post-translationally modified peptides from tandem mass spectrometry data, while expression of BURP-domain precursor genes in Nicotiana benthamiana enabled source-plant-independent biosynthesis. Finally, multiplexed fluorescence imaging of peptide-treated cancer cells provided morphological information to assess cytotoxicity and infer their mechanism of action. These studies collectively illustrate the power of integrating multi-omic strategies with high-content analysis and establishes a scalable workflow for expanding the chemical space of bioactive cyclic plant peptides.
- 일반주제명
- Oncology
- 일반주제명
- Analytical chemistry
- 일반주제명
- Biochemistry
- 일반주제명
- Plant sciences
- 일반주제명
- Pharmaceutical sciences
- 기타저자
- University of Michigan Medicinal Chemistry
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798291568620
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■035 ▼a(MiAaPQ)umichrackham006467
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.99
■1001 ▼aShafiq, Khadija.
■24510▼aMulti-Omics and High-Content Screening for the Discovery of Plant Cyclic Peptides in Cancer Drug Development
■260 ▼a[Sl]▼bUniversity of Michigan▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a219 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Kersten, Roland D.;Sexton, Jonathan Z.
■5021 ▼aThesis (Ph.D.)--University of Michigan, 2025.
■520 ▼aOver the past century, nearly half of the FDA-approved drugs were sourced from natural products, with plants representing a prolific reservoir of chemotherapeutics. Among these, cyclic peptides have emerged as promising scaffolds for cancer drug discovery, offering the metabolic stability and target specificity of biologics alongside the oral bioavailability and membrane permeability of small molecules. Despite their promise, plant natural product drug discovery has been deprioritized by the pharmaceutical industry due to three persistent bottlenecks: (1) low-yield isolation from source plant material, (2) chemical rediscovery in bioactivity-guided fractionation, and (3) synthetic barriers to macrocyclic complexity and lead diversification. This dissertation addresses these challenges through an integrated multi-omics strategy that combines metabolomics, genome mining, proteomics, and metabolic engineering to identify novel cyclic peptides from plant sequencing data. Additionally, a high-content screening (HCS) platform was developed to evaluate the cytotoxicity profiles of these peptides in cell-based cancer models. The integrated multi-omics and HCS approach led to the discovery of cyclic peptides from three distinct classes of ribosomally synthesized and post-translationally modified peptides (RiPPs): a cyclopeptide alkaloid, multiple stephanotic acid peptides, and two cysteine-rich peptides. These peptides, collectively termed burpitides, are cyclized by copper-dependent BURP-domain-containing proteins (burpitide cyclases) encoded within the same precursor gene as their peptide substrates. This genomic architecture enables discovery via sequence-based mining of plant genomes and transcriptomes. Proteome database search tools facilitated the detection of post-translationally modified peptides from tandem mass spectrometry data, while expression of BURP-domain precursor genes in Nicotiana benthamiana enabled source-plant-independent biosynthesis. Finally, multiplexed fluorescence imaging of peptide-treated cancer cells provided morphological information to assess cytotoxicity and infer their mechanism of action. These studies collectively illustrate the power of integrating multi-omic strategies with high-content analysis and establishes a scalable workflow for expanding the chemical space of bioactive cyclic plant peptides.
■590 ▼aSchool code: 0127.
■650 4▼aOncology
■650 4▼aAnalytical chemistry
■650 4▼aBiochemistry
■650 4▼aPlant sciences
■650 4▼aPharmaceutical sciences
■653 ▼aNatural product chemistry
■653 ▼aMass spectrometry
■653 ▼aHigh-content screening
■653 ▼aPlant cyclic peptides
■653 ▼aBurpitide cyclases
■690 ▼a0992
■690 ▼a0486
■690 ▼a0487
■690 ▼a0479
■690 ▼a0572
■71020▼aUniversity of Michigan▼bMedicinal Chemistry.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0127
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17359947▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
