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Rational Design of Selective Protein Therapeutics for Structurally and Functionally Complex Targets.
Rational Design of Selective Protein Therapeutics for Structurally and Functionally Complex Targets.
상세정보
- 자료유형
- 학위논문(국외)
- 기본표목-개인명
- 표제와 책임표시사항
- Rational Design of Selective Protein Therapeutics for Structurally and Functionally Complex Targets.
- 발행, 배포, 간사 사항
- 발행, 배포, 간사 사항
- 형태사항
- 211 p.
- 일반주기
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 일반주기
- Includes supplementary digital materials.
- 일반주기
- Advisor: Silver, Pamela A.
- 학위논문주기
- Thesis (Ph.D.)--Harvard University, 2025.
- 요약 등 주기
- 요약Protein biologics have transformed modern drug discovery and development by offering high selectivity and reduced off-target effects, prolonged serum half-lives, and the ability to modulate cellular processes. However, many clinically relevant targets remain intractable due to limited structural or mechanistic information, selectivity issues, or the need to modulate multiple pathways simultaneously. This work presents two distinct case studies in engaging challenging targets using rationally designed bispecific protein therapeutics and Fc fusion proteins. In Chapter 1, I describe the successful design and characterization of the first non-EPO-based, bispecific agonists for the tissue-protective receptor, EPO-R/CD131. We generated a structural model of the EPO-R/CD131 complex using AlphaFold and available structures of EPO-R and CD131 individually bound to single chain variable fragments (scFvs). Using this model, we designed several tandem scFvs and a bispecific antibody that selectively activated EPO-R/CD131 and not the related receptor, EPO-R/EPO-R. These proteins serve as a foundation for future studies of EPO-R/CD131 biology or for the development of safer, more selective therapeutic candidates for cell-protection applications, such as neurodegenerative diseases. In Chapter 2, I detail the design and early stage testing of several mono- and bi-specific Fc fusion proteins for the treatment of dysfunctional and inflammatory pain. Using similar design principles, I generated Fc fusions to peptides that inhibit the voltage-gated sodium channels Nav1.7 and Nav1.8 and Fc fusions to neprilysin, an enzyme that degrades the neuroinflammatory peptide, substance P. Altogether, this work provides novel approaches to the modulation of these challenging targets and insights about future design considerations and possible solutions to further the development of protein therapeutics for cell-protection and chronic pain.
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 부출표목-단체명
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 원문정보보기
MARC
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■1001 ▼aDoiron, Kailyn E.▼0(orcid)0000-0001-5208-788X
■24510▼aRational Design of Selective Protein Therapeutics for Structurally and Functionally Complex Targets.
■260 ▼a[S.l.]▼bHarvard University. ▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a211 p.
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aIncludes supplementary digital materials.
■500 ▼aAdvisor: Silver, Pamela A.
■5021 ▼aThesis (Ph.D.)--Harvard University, 2025.
■520 ▼aProtein biologics have transformed modern drug discovery and development by offering high selectivity and reduced off-target effects, prolonged serum half-lives, and the ability to modulate cellular processes. However, many clinically relevant targets remain intractable due to limited structural or mechanistic information, selectivity issues, or the need to modulate multiple pathways simultaneously. This work presents two distinct case studies in engaging challenging targets using rationally designed bispecific protein therapeutics and Fc fusion proteins. In Chapter 1, I describe the successful design and characterization of the first non-EPO-based, bispecific agonists for the tissue-protective receptor, EPO-R/CD131. We generated a structural model of the EPO-R/CD131 complex using AlphaFold and available structures of EPO-R and CD131 individually bound to single chain variable fragments (scFvs). Using this model, we designed several tandem scFvs and a bispecific antibody that selectively activated EPO-R/CD131 and not the related receptor, EPO-R/EPO-R. These proteins serve as a foundation for future studies of EPO-R/CD131 biology or for the development of safer, more selective therapeutic candidates for cell-protection applications, such as neurodegenerative diseases. In Chapter 2, I detail the design and early stage testing of several mono- and bi-specific Fc fusion proteins for the treatment of dysfunctional and inflammatory pain. Using similar design principles, I generated Fc fusions to peptides that inhibit the voltage-gated sodium channels Nav1.7 and Nav1.8 and Fc fusions to neprilysin, an enzyme that degrades the neuroinflammatory peptide, substance P. Altogether, this work provides novel approaches to the modulation of these challenging targets and insights about future design considerations and possible solutions to further the development of protein therapeutics for cell-protection and chronic pain.
■590 ▼aSchool code: 0084.
■650 4▼aBioengineering.
■650 4▼aMolecular biology.
■650 4▼aPharmaceutical sciences.
■653 ▼aErythropoietin
■653 ▼aFc fusion
■653 ▼aFusion proteins
■653 ▼aProtein engineering
■653 ▼aSingle chain variable fragments
■653 ▼aSynthetic biology
■690 ▼a0202
■690 ▼a0307
■690 ▼a0572
■71020▼aHarvard University▼bSystems Biology.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0084
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357403▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
