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| Status |
Public on Sep 21, 2022 |
| Title |
Nanomolar inhibition of SARS-CoV-2 infection by N-terminally extended HR2 peptides |
| Organism |
Severe acute respiratory syndrome coronavirus 2 |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available COVID-19 vaccines and monoclonal antibody therapies through changes of epitopes on the receptor binding domain of the viral spike glycoprotein (S). Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors which block formation of the HR1HR2 six-helix bundle of the SARS-CoV-2 spike protein and thus interfere with viral membrane fusion; HR2 derived peptides are validated inhibitors of this process. Here, we identify a short N-terminal region that, when appended to the helical region of an HR2 peptide from previous studies, leads to potent inhibition of fusion. The extended peptide shows an ~100-fold increase in efficacy compared with the previously used 36-amino-acid version of HR2, effectively achieving single-digit nanomolar inhibition of SARS-CoV-2 in cell-based fusion, VSV-SARS-CoV-2 chimera, and authentic SARS-CoV-2 infection assays. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. Structural studies of the HR1HR2 bundle reveal the formation of an extended, stabilized N-terminus that interacts with the HR2 triple helix, further stabilizing the HR1HR2 bundle. Together, these results suggest that regions outside the previously studied HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants.
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| Overall design |
High-throughput screening for peptide binders of the HR1-portion of the spike protein using mRNA display
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| Contributor(s) |
Yang K, Wang C, Kreutzberger AJ, Ojha R, Kuivanen S, Couoh S, White KI, Held R, Pfuetzner RA, Esquivies L, Muratcioglu S, Eisen TJ, Subramanian S, Marcus K, Kuriyan J, Vapalahti O, Balistreri G, Kirchhausen T, Brunger AT |
| Citation(s) |
36122200 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AI163019 |
Mechanism and Inhibition of SARS-CoV-2 Entry |
WASHINGTON UNIVERSITY |
TOMAS KIRCHHAUSEN |
| R35 GM130386 |
VISUALIZATION OF SUBCELLULAR DYNAMICS IN MULTICELLULAR ORGANISMS |
CHILDREN'S HOSPITAL |
TOMAS KIRCHHAUSEN |
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| Submission date |
May 17, 2022 |
| Last update date |
Oct 27, 2022 |
| Contact name |
Timothy J Eisen |
| E-mail(s) |
timeisen@berkeley.edu
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| Organization name |
UC Berkeley
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| Department |
QB3
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| Lab |
John Kuriyan
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| Street address |
Stanley Hall
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| City |
Berkeley |
| State/province |
CALIFORNIA |
| ZIP/Postal code |
94720 |
| Country |
USA |
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| Platforms (1) |
| GPL28866 |
Illumina MiSeq (Severe acute respiratory syndrome coronavirus 2) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA839099 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE203229_OligoSequences.txt.gz |
40.9 Kb |
(ftp)(http) |
TXT |
| GSE203229_RAW.tar |
10.0 Kb |
(http)(custom) |
TAR (of TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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