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Supercoiling Structure-Based Design of a Trimeric Coiled-Coil Peptide with High Potency against HIV-1 and Human β-Coronavirus Infection.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Feb 24; Vol. 65 (4), pp. 2809-2819. Date of Electronic Publication: 2021 Apr 30. - Publication Year :
- 2022
-
Abstract
- Hexameric structure formation through packing of three C-terminal helices and an N-terminal trimeric coiled-coil core has been proposed as a general mechanism of class I enveloped virus entry. In this process, the C-terminal helical repeat (HR2) region of viral membrane fusion proteins becomes transiently exposed and accessible to N-terminal helical repeat (HR1) trimer-based fusion inhibitors. Herein, we describe a mimetic of the HIV-1 gp41 HR1 trimer, N3G, as a promising therapeutic against HIV-1 infection. Surprisingly, we found that in addition to protection against HIV-1 infection, N3G was also highly effective in inhibiting infection of human β-coronaviruses, including MERS-CoV, HCoV-OC43, and SARS-CoV-2, possibly by binding the HR2 region in the spike protein of β-coronaviruses to block their hexameric structure formation. These studies demonstrate the potential utility of anti-HIV-1 HR1 peptides in inhibiting human β-coronavirus infection. Moreover, this strategy could be extended to the design of broad-spectrum antivirals based on the supercoiling structure of peptides.
- Subjects :
- Antiviral Agents chemical synthesis
Antiviral Agents chemistry
Cell Line
Coronavirus Infections metabolism
Dose-Response Relationship, Drug
HIV Envelope Protein gp41 metabolism
HIV-1 metabolism
Humans
Microbial Sensitivity Tests
Peptides chemical synthesis
Peptides chemistry
Structure-Activity Relationship
Antiviral Agents pharmacology
Coronavirus Infections drug therapy
Drug Design
HIV Envelope Protein gp41 antagonists & inhibitors
HIV-1 drug effects
Peptides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33929200
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00258