دورية أكاديمية
أعرض في EDS

Design and characterization of ebolavirus GP prehairpin intermediate mimics as drug targets.

التفاصيل البيبلوغرافية
العنوان: Design and characterization of ebolavirus GP prehairpin intermediate mimics as drug targets.
المؤلفون: Clinton TR; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, 84112-5650., Weinstock MT, Jacobsen MT, Szabo-Fresnais N, Pandya MJ, Whitby FG, Herbert AS, Prugar LI, McKinnon R, Hill CP, Welch BD, Dye JM, Eckert DM, Kay MS
المصدر: Protein science : a publication of the Protein Society [Protein Sci] 2015 Apr; Vol. 24 (4), pp. 446-63. Date of Electronic Publication: 2014 Oct 31.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
أسماء مطبوعة: Publication: 2001- : Woodbury, NY : Cold Spring Harbor Laboratory Press
Original Publication: New York, N.Y. : Cambridge University Press, c1992-
مواضيع طبية MeSH: Ebolavirus/*chemistry , Viral Envelope Proteins/*chemistry , Viral Envelope Proteins/*metabolism, Amino Acid Sequence ; Drug Delivery Systems ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Sequence Alignment ; Viral Envelope Proteins/genetics
مستخلص: Ebolaviruses are highly lethal filoviruses that cause hemorrhagic fever in humans and nonhuman primates. With no approved treatments or preventatives, the development of an anti-ebolavirus therapy to protect against natural infections and potential weaponization is an urgent global health need. Here, we describe the design, biophysical characterization, and validation of peptide mimics of the ebolavirus N-trimer, a highly conserved region of the GP2 fusion protein, to be used as targets to develop broad-spectrum inhibitors of ebolavirus entry. The N-trimer region of GP2 is 90% identical across all ebolavirus species and forms a critical part of the prehairpin intermediate that is exposed during viral entry. Specifically, we fused designed coiled coils to the N-trimer to present it as a soluble trimeric coiled coil as it appears during membrane fusion. Circular dichroism, sedimentation equilibrium, and X-ray crystallography analyses reveal the helical, trimeric structure of the designed N-trimer mimic targets. Surface plasmon resonance studies validate that the N-trimer mimic binds its native ligand, the C-peptide region of GP2. The longest N-trimer mimic also inhibits virus entry, thereby confirming binding of the C-peptide region during viral entry and the presence of a vulnerable prehairpin intermediate. Using phage display as a model system, we validate the suitability of the N-trimer mimics as drug screening targets. Finally, we describe the foundational work to use the N-trimer mimics as targets in mirror-image phage display, which will be used to identify D-peptide inhibitors of ebolavirus entry.
(© 2014 The Protein Society.)
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معلومات مُعتمدة: P50 GM082545 United States GM NIGMS NIH HHS; GM82545 United States GM NIGMS NIH HHS; AI102347 United States AI NIAID NIH HHS; R44 AI102347 United States AI NIAID NIH HHS; R43 AI102347 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: N-trimer; designed coiled coil; ebolavirus; ebolavirus GP2; filovirus entry; mirror-image phage display; phage display; prehairpin intermediate
المشرفين على المادة: 0 (Viral Envelope Proteins)
0 (envelope glycoprotein, Ebola virus)
تواريخ الأحداث: Date Created: 20141008 Date Completed: 20160104 Latest Revision: 20230106
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC4380977
DOI: 10.1002/pro.2578
PMID: 25287718
قاعدة البيانات: MEDLINE
الوصف
تدمد:1469-896X
DOI:10.1002/pro.2578