CGM23 corresponds to a pan-coronavirus lipopeptide inhibitor potently inhibiting virion fusion - PubMed (original) (raw)

. 2026 Mar 11;29(4):115334.

doi: 10.1016/j.isci.2026.115334. eCollection 2026 Apr 17.

Roland Schwarzer 1 2 3, Mauricio Montano 1 2, Ekram W Helmy 1 2, Rahul K Suryawanshi 1 4, Taha Y Taha 1 2 5, Yan Wang 6, Yvonne Angel 6, Marc Adler 6, M Flori Sassano 7, Hyunil Jo 8, Robert Tarran 7, Melanie Ott 1 2 9, Warner C Greene 1 2 9 10

Affiliations

CGM23 corresponds to a pan-coronavirus lipopeptide inhibitor potently inhibiting virion fusion

Yusuke Matsui et al. iScience. 2026.

Abstract

We developed a pan-coronavirus lipopeptide fusion inhibitor, CGM23, which binds to the highly conserved spike heptad repeat-1 domain, thus interrupting the formation of the six-helix bundle required for membrane fusion. In vitro, CGM23 potently inhibited infection by all human coronaviruses tested, including SARS-CoV, MERS-CoV, and SARS-CoV-2 and the seasonal coronaviruses. CGM23 is based on the amino acid sequence of SARS-CoV-2 spike protein. Computational modeling, 4-phenylbutanoic acid was appended to the N-terminus to mimic interactions with the hydrophobic pocket adjacent to the heptad repeat-2. A C-terminal addition of palmitic acid via a PEG linker enhanced CGM23's fusion inhibition. In a wild-type mouse model infected with mouse-adapted SARS-CoV-2, intranasal CGM23 prevented lung infection when given 30 min before challenge. Furthermore, therapeutic CGM23 8 h post-inoculation significantly reduced viral loads in the lungs. In summary, CGM23 represents a promising pan-coronavirus inhibitor with both potential therapeutic and prophylactic activity in humans.

Keywords: Biochemistry; Pharmacology; Virology.

© 2026 The Authors.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None

Graphical abstract

Figure 1

Figure 1

Peptide design and evaluation (A) Schematic representation of SARS-CoV-2 spike protein and amino acid sequences of HR2 peptides from SARS-CoV-2 and EK1 (HCoV-OC43 HR2 derived peptide). N, N-terminus; C, C-terminus; S1/S2, cleavage site at S1/S2 boundary; RBD, receptor-binding domain; HR1, heptad repeat 1; HR2, heptad repeat 2; HR2P, heptad repeat 2 peptide. Syncytia assay. Left: GFP- and spike-expressing 293T cells were co-cultured with RFP- and ACE2-expressing Calu-6 cells for 16 h in the presence or absence of peptides. Center: double-positive cells (white arrows) indicative of syncytia formation are frequent in the presence of the scrambled EK1 peptide (Ⅰ) but not in the presence of CGM23 (Ⅱ) (100 nM). Right: quantification of syncytia formation in the presence of the scrambled EK1 peptide (top) or CGM23 (bottom) relative to mock treatment. (B) Sequence, N- and C-terminal modifications and IC50 of the 15 peptides with IC50s < 10 nM in the syncytia assay. CoV-2, SARS-CoV-2; N-term, N-terminus; C-term, C-terminus. IC50 data are means of samples from a representative experiment. Ac, acetylation; PPA, 4-phenylpropanoic acid; PBA, 4-phenylbutanonic acid. (C) Correlation between IC50 values in the pseudotyped SARS-CoV-2 spike virion assay and live SARS-CoV2 virus infection assay for the 15 peptides with IC50 values below 10 nM in the syncytia assay. Statistical analysis was performed using Spearman’s rank test. (D and E) Dose-dependent inhibitory activity of CGM23 and EK1C4 relative to CG167 (EK1 scrambled peptide with EK1C4 lipidation) in the pseudotyped SARS-CoV2 spike virion assay (D) and live SARS-CoV2 infection assay (E). IC50, half-maximal inhibitory concentration.

Figure 2

Figure 2

Antiviral activity of CGM23 against coronaviruses other than SARS-CoV-2 and SARS-CoV-2 variants (A–D) Inhibitory activity of CGM23 and EK1C4 in the pseudotyped spike virion assay against HCoV-229E (A) HCoV-NL63 (B), SARS-CoV (C), and MERS-CoV (D). CG167, EK1 scrambled peptide with EK1C4 lipidation. (E and F) Inhibitory activity of EK1C4 (E) and CGM23 (F) against SARS-CoV-2 variants in the pseudotyped spike virion assay. IC50, half-maximal inhibitory concentration. Ambig, ambiguous.

Figure 3

Figure 3

CGM23 stability against plasma and enzymes and pharmacodynamics (A–F), Stability of peptides in plasma (A) or in the presence of cathepsin D (B), cathepsin B (C), cathepsin K (D), neutrophil elastase (E), trypsin (F) in vitro. After incubation of peptides with plasma or enzymes for 8 h, the residual amount of peptides was determined by HPLC. (G) Time course of CGM23 and EK1C4 concentration in plasma (LLOQ; 8.65 ng/ml) after intranasal administration to mice (CGM23, 0.865 mg/kg; EK1C4, 1 mg/kg). ∗p < 0.05. Statistical analysis was performed using unpaired two-tailed Student’s t test test. Black bars represent the mean concentrations. LLOQ, lower limit of quantification. Identical symbols indicate sequential samples from the same mouse.

Figure 4

Figure 4

In vivo prophylactic and therapeutic efficacy of CGM23 against SARS-CoV-2 live virus in mice (A) The SARS-CoV-2 outgrowth assay. Lung homogenates were collected 2 days post viral infection (DPI) combined with intranasal administration of CGM23 and EK1C4 (12.5 μg, 0.865 mg/kg). (B) Diluted lung homogenates were added to Calu-6-ACE2 cells and infection titers were measured by the luciferase assay 48 h later. CG167, EK1 scrambled peptide with EK1C4 lipidation. Data presented correspond to mean ± SD. ∗p < 0.05. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test. (C) Histopathological findings of mouse lungs at 2 days after virus inoculation. Images are shown clockwise starting from the top left: CG167 group, EK1C4 group, non-infected group, and CGM23 group. Lung sections were stained with anti-spike antibody (green) and anti-MAC-2 antibody (magenta) and DAPI (blue). Scale bars, 100μm. (D and E) Quantitative analysis of lung histopathological findings for each group. Data shown represent means ± SD. (F) Therapeutic treatment. CGM23 and EK1C4 were administered intranasally (12.5 μg, 0.865 mg/kg; 25 μg, 1.73 mg/kg) 8 h after SARS-CoV-2 inoculation, and lung homogenates were collected 24 h later for plaque assay analysis. Data presented correspond to mean ± SD. ∗p < 0.05, ∗∗∗p < 0.001. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test. (G) Prophylactic treatment. SARS-CoV-2 was administered intranasally 30 min after intranasal administration of CGM23 or EK1C4 (12.5 μg, 0.865 mg/kg; 25 μg, 1.73 mg/kg). Lung tissues were collected 24 h later for plaque assay analysis.

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