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From Hit Discovery to Lead Optimization: The Rational Design and Synthesis of Entry Inhibitors Targeting HIV-1 and SARS-COV-2
From Hit Discovery to Lead Optimization: The Rational Design and Synthesis of Entry Inhibitors Targeting HIV-1 and SARS-COV-2
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103154
- ISBN
- 9798280759589
- DDC
- 547
- 저자명
- Yang, Derek.
- 서명/저자
- From Hit Discovery to Lead Optimization: The Rational Design and Synthesis of Entry Inhibitors Targeting HIV-1 and SARS-COV-2
- 발행사항
- [Sl] : University of Pennsylvania, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 539 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Huryn, Donna;Smith, Amos B., III.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2025.
- 초록/해제
- 요약With an estimated 40 million people currently living with HIV-1 and the flagship treatment regimen, antiretroviral therapy (ART), facing challenges such as it's inability to eradicate the disease thereby necessitating lifelong dependence on treatment, there exists a need for a novel class of drugs that can address the shortcomings presented by the currently approved therapeutics. CD4 mimetic compounds (CD4mcs) are small molecules that mimic the host's natural HIV-1 receptor, CD4, and are able to bind to the CD4 binding site of the envelope glycoprotein (Env) to induce premature and irreversible conformational changes that inactivates the virus. Furthermore, these conformational changes leave the Env vulnerable to neutralization via antibody dependent cellular cytotoxicity (ADCC) rendering this as an avenue for a potentially curative therapeutic. In the first part of this thesis, the development indoline based CD4mcs are investigated by modifying various regions of the scaffold to form better interactions with the gp120 binding pocket. This structure-activity relationship (SAR) study was guided by in silico predictions and evaluated by X-ray crystallography and in vitro assays.The second part of this thesis is about the identification and development of a novel class of compounds used to inhibit SARS-CoV-2 entry. It is no secret the impacts that COVID-19 had on society, while there are dozens of authorized drugs and treatment options each one of them comes with shortcomings, especially as the virus evolved to the Omicron variant. As such even today, there exists a need for additional therapeutics. Our group repurposed a compound, VE607, that was identified as a SARS-CoV entry inhibitor and discovered that it showed activity against SARS-CoV-2. Thereafter, our work has been dedicated to the elaboration of this scaffold to ascertain its mechanism of action as well as to develop it further as a preclinical candidate. The work presented in this part involves the systematic modification of VE607 that resulted in a more potent analog that we were able to advance to in vivo studies.
- 일반주제명
- Organic chemistry
- 일반주제명
- Chemistry
- 일반주제명
- Pharmaceutical sciences
- 일반주제명
- Biochemistry
- 키워드
- Aids
- 기타저자
- University of Pennsylvania Chemistry
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a547
■1001 ▼aYang, Derek.
■24510▼aFrom Hit Discovery to Lead Optimization: The Rational Design and Synthesis of Entry Inhibitors Targeting HIV-1 and SARS-COV-2
■260 ▼a[Sl]▼bUniversity of Pennsylvania▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a539 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Huryn, Donna;Smith, Amos B., III.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2025.
■520 ▼aWith an estimated 40 million people currently living with HIV-1 and the flagship treatment regimen, antiretroviral therapy (ART), facing challenges such as it's inability to eradicate the disease thereby necessitating lifelong dependence on treatment, there exists a need for a novel class of drugs that can address the shortcomings presented by the currently approved therapeutics. CD4 mimetic compounds (CD4mcs) are small molecules that mimic the host's natural HIV-1 receptor, CD4, and are able to bind to the CD4 binding site of the envelope glycoprotein (Env) to induce premature and irreversible conformational changes that inactivates the virus. Furthermore, these conformational changes leave the Env vulnerable to neutralization via antibody dependent cellular cytotoxicity (ADCC) rendering this as an avenue for a potentially curative therapeutic. In the first part of this thesis, the development indoline based CD4mcs are investigated by modifying various regions of the scaffold to form better interactions with the gp120 binding pocket. This structure-activity relationship (SAR) study was guided by in silico predictions and evaluated by X-ray crystallography and in vitro assays.The second part of this thesis is about the identification and development of a novel class of compounds used to inhibit SARS-CoV-2 entry. It is no secret the impacts that COVID-19 had on society, while there are dozens of authorized drugs and treatment options each one of them comes with shortcomings, especially as the virus evolved to the Omicron variant. As such even today, there exists a need for additional therapeutics. Our group repurposed a compound, VE607, that was identified as a SARS-CoV entry inhibitor and discovered that it showed activity against SARS-CoV-2. Thereafter, our work has been dedicated to the elaboration of this scaffold to ascertain its mechanism of action as well as to develop it further as a preclinical candidate. The work presented in this part involves the systematic modification of VE607 that resulted in a more potent analog that we were able to advance to in vivo studies.
■590 ▼aSchool code: 0175.
■650 4▼aOrganic chemistry
■650 4▼aChemistry
■650 4▼aPharmaceutical sciences
■650 4▼aBiochemistry
■653 ▼aAids
■653 ▼aMedicinal chemistry
■653 ▼aStructure activity relationship
■653 ▼aEnvelope glycoprotein
■690 ▼a0490
■690 ▼a0487
■690 ▼a0572
■690 ▼a0485
■71020▼aUniversity of Pennsylvania▼bChemistry.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357243▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
