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Engineering and Evolving Helical Proteins That Improve in Vivo Stability and Inhibit Entry of Enfuvirtide-Resistant HIV-1
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Engineering and Evolving Helical Proteins That Improve in Vivo Stability and Inhibit Entry of Enfuvirtide-Resistant HIV-1. |
| 개인저자 | Walker, Susanne N. |
| 단체저자명 | Colorado State University. Chemistry. |
| 발행사항 | [S.l.]: Colorado State University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 146 p. |
| 기본자료 저록 | Dissertations Abstracts International 80-12B. Dissertation Abstract International |
| ISBN | 9781392276709 |
| 학위논문주기 | Thesis (Ph.D.)--Colorado State University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Publisher info.: Dissertation/Thesis. Advisor: Kennan, Alan. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Methods for the stabilization of well-defined helical peptide drugs and basic research tools have received considerable attention in the last decade. Enfuvirtide is a 36-residue chemically synthesized helical peptide that targets the viral gp41 protein and inhibits viral membrane fusion. Enfuvirtide-resistant HIV, however, has been prolific, and this peptide therapy requires daily injection due to proteolytic degradation.In this dissertation I have developed a method for stabilizing helical peptide therapeutics termed helix-grafted display proteins. These consist of the HIV-1 gp41 C-peptide helix grafted onto Pleckstrin Homology domains. Some of these earlier protein biologics inhibit HIV-1 entry with modest and variable potencies (IC50 190 nM - >1 關M). After optimization of the scaffold and the helix, our designer peptide therapeutic potently inhibited HIV-1 entry in a live-virus assay (IC50 1.9-12.4 nM). Sequence optimization of solvent-exposed helical residues using yeast display as a screening method led to improved biologics with enhanced protein expression in Escherichia coli (E. coli, a common bio-expression host), with no appreciable change in viral membrane fusion suppression. Optimized proteins suppress the viral entry of a clinically-relevant double mutant of HIV-1 that is gp41 C-peptide sensitive and Enfuvirtide-resistant. Protein fusions engineered for serum-stability also potently inhibit HIV-1 entry. |
| 일반주제명 | Chemistry. |
| 언어 | 영어 |
| 바로가기 | 
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