Journal article
Peptide Triazole Thiol Irreversibly Inactivates Metastable HIV-1 Env by Accessing Conformational Triggers Intrinsic to Virus–Cell Entry
Microorganisms (Basel), v 9(6), p1286
12 Jun 2021
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
KR13, a peptide triazole thiol previously established to inhibit HIV-1 infection and cause virus lysis, was evaluated by flow cytometry against JRFL Env-presenting cells to characterize induced Env and membrane transformations leading to irreversible inactivation. Transiently transfected HEK293T cells were preloaded with calcein dye, treated with KR13 or its thiol-blocked analogue KR13b, fixed, and stained for gp120 (35O22), MPER (10E8), 6-helix-bundle (NC-1), immunodominant loop (50-69), and fusion peptide (VRC34.01). KR13 induced dose-dependent transformations of Env and membrane characterized by transient poration, MPER exposure, and 6-helix-bundle formation (analogous to native fusion events), but also reduced immunodominant loop and fusion peptide exposure. Using a fusion peptide mutant (V504E), we found that KR13 transformation does not require functional fusion peptide for poration. In contrast, simultaneous treatment with fusion inhibitor T20 alongside KR13 prevented membrane poration and MPER exposure, showing that these events require 6-helix-bundle formation. Based on these results, we formulated a model for PTT-induced Env transformation portraying how, in the absence of CD4/co-receptor signaling, PTT may provide alternate means of perturbing the metastable Env-membrane complex, and inducing fusion-like transformation. In turn, the results show that such transformations are intrinsic to Env and can be diverted for irreversible inactivation of the protein complex.
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Details
- Title
- Peptide Triazole Thiol Irreversibly Inactivates Metastable HIV-1 Env by Accessing Conformational Triggers Intrinsic to Virus–Cell Entry
- Creators
- Charles Gotuaco Ang - Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, PA 19102, USAErik Carter - Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, PA 19102, USAAnn Haftl - Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, PA 19102, USAShiyu Zhang - Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, PA 19102, USAAdel A Rashad - Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, PA 19102, USAMichele Kutzler - Departments of Medicine and Microbiology and Immunology, College of Medicine, Drexel University, Philadelphia, PA 19102, USACameron F Abrams - Department of Chemical and Biological Engineering, College of Engineering, Drexel University, Philadelphia, PA 19102, USAIrwin M Chaiken - Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, PA 19102, USA
- Publication Details
- Microorganisms (Basel), v 9(6), p1286
- Publisher
- MDPI
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Infectious Diseases (and HIV Medicine); Chemical and Biological Engineering; Chemistry
- Web of Science ID
- WOS:000666960000001
- Scopus ID
- 2-s2.0-85107655814
- Other Identifier
- 991015238575004721
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- Web of Science research areas
- Microbiology