RSC Chemical Biology, Journal Year: 2023, Volume and Issue: 5(2), P. 131 - 140
Published: Nov. 7, 2023
Peptide inhibitors against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are designed using a screening system for peptide-based containing an α-helix region (SPICA) and structures predicted by AlphaFold2.
Language: Английский
Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)
Published: Jan. 15, 2025
Abstract We have assessed antiviral activity and induction of protective immunity fusion-inhibitory lipopeptides derived from the C-terminal heptad-repeat domain SARS-CoV-2 spike glycoprotein in transgenic mice expressing human ACE2 (K18-hACE2). The block infection cell lines lung-derived organotypic cultures. Intranasal administration allows maintenance homeostatic transcriptomic immune profile lungs, prevents body-weight loss, decreases viral load shedding, protects death caused by variants. Prolonged high-dose has neither adverse effects nor impairs peptide efficacy subsequent challenges. peptide-protected develop cross-reactive neutralizing antibodies against both used for initial recently circulating variants, are completely protected a second lethal infection, suggesting that they developed SARS-CoV-2-specific immunity. This strategy provides an additional approach global effort COVID-19 may contribute to development rapid responses emerging pathogenic viruses.
Language: Английский
Citations
1
Science China Life Sciences, Journal Year: 2023, Volume and Issue: 66(10), P. 2201 - 2213
Published: Aug. 11, 2023
Language: Английский
Citations
15
MedComm, Journal Year: 2024, Volume and Issue: 5(8)
Published: July 28, 2024
Abstract Development of potent and broad‐spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains one the top priorities, especially in cases emergence mutant viruses inability current vaccines to prevent viral transmission. In this study, we have generated a novel membrane fusion‐inhibitory lipopeptide IPB29, which is currently under clinical trials; herein, report its design strategy preclinical data. First, surprisingly found that IPB29 with rigid linker between peptide sequence lipid molecule had greatly improved α‐helical structure antiviral activity. Second, potently inhibited large panel SARS‐CoV‐2 variants including previously circulating viruses, such as Omicron XBB.5.1 EG.5.1. Third, could also cross‐neutralize bat‐ pangolin‐isolated SARS‐CoV‐2‐related CoVs (RatG13, PCoV‐GD, PCoV‐GX) other human (SARS‐CoV, MERS‐CoV, HCoV‐NL63, HCoV‐229E). Fourth, administrated an inhalation solution (IPB29‐IS) Syrian hamsters exhibited high therapeutic preventive efficacies Delta or variant. Fifth, pharmacokinetic profiles safety pharmacology IPB29‐IS were extensively characterized, providing data support evaluation humans. conclusion, our studies demonstrated for fusion inhibitors offered ideal drug candidate coronaviruses.
Language: Английский
Citations
4
Biosafety and Health, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 1, 2025
Language: Английский
Citations
0
Journal of Virology, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 4, 2025
ABSTRACT SARS-CoV-2 poses an ongoing threat to human health as variants continue emerge. Several effective vaccines are available, but a diminishing number of Americans receive the updated (only 22% received 2023 update). Public hesitancy towards and common occurrence “breakthrough” infections (i.e. , vaccinated individuals) highlight need for alternative methods reduce viral transmission. enters cells by fusing its envelope with target cell membrane in process mediated spike protein, S. The S protein operates via Class I fusion mechanism which between host is structural rearrangements trimer. We previously reported lipopeptides derived from C-terminal heptad repeat (HRC) domain that potently inhibit SARS-CoV-2, both vitro vivo . These bear attached cholesterol unit anchor them membrane. Here, improve prospects experimental development future clinical utility, we employed structure-guided design incorporate charged residues at specific sites peptide enhance aqueous solubility. This effort resulted two new, potent lipopeptide inhibitors. IMPORTANCE Despite existence constant evolution new breakthrough antiviral approaches. have shown designed bind conserved region on can effectively block entry into thereby infection. To support feasibility using this approach humans, re-designed these be more soluble, information about structure interacting peptides modify chain. against MERS. described here could serve treatment people who unvaccinated or experience infections, increasing solubility applied broad spectrum treating emerging viruses.
Language: Английский
Citations
0
Antiviral Research, Journal Year: 2025, Volume and Issue: unknown, P. 106154 - 106154
Published: March 1, 2025
Language: Английский
Citations
0
PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(4), P. e1012808 - e1012808
Published: April 8, 2025
Although structures of pre- and post-fusion conformations SARS-CoV-2 spikes have been solved by cryo-electron microscopy, the transient spike that mediate virus fusion with host cell membranes remain poorly understood. In this study, we used a peptide inhibitor corresponding to heptad repeat 2 (HR2) in S2 transmembrane subunit investigate fusion-intermediate involve exposure highly conserved 1 (HR1). The HR2 disrupts assembly HR1 regions spike, which form six-helix bundle during transition conformation. We show binding S1 ACE2 is sufficient induce conformational changes allow shedding enable bind inhibit membrane fusion. When TMPRSS2 also present, captures an S2’ intermediate though proportion relative lower Omicron variants than pre-Omicron variants. lacking natural S1/S2 furin cleavage site, alone not for trapping intermediates, but presence allows intermediate. These results indicate that, addition engagement, at least one needed unwinding into peptide-sensitive, Our findings elucidate expose sites on could be targeted inhibitors or antibodies.
Language: Английский
Citations
0
3 Biotech, Journal Year: 2025, Volume and Issue: 15(2)
Published: Jan. 13, 2025
Language: Английский
Citations
0
Published: April 25, 2023
Predictions generated by evolutionary docking of star-shaped ligands targeting the prefusion state Omicron variants are described here. For this, one selected molecule previously identified with seeSAR program, was used as parent to randomly generate made-on-demand large children libraries for best fitting spike top-to-bottom inner-cavity DataWarrior subprogram. The docking-scores were consensed AutoDockVina ranks normalized molecular size and hydrophobicity. These explorations new main chemotype improved specificity exceptional nanomolar affinities, predicting aqueous soluble molecules trimeric alpha-helices.
Language: Английский
Citations
7
International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 262, P. 130132 - 130132
Published: Feb. 12, 2024
Inhibition of SARS-CoV-2 membrane fusion is a highly desired target to combat COVID-19. The interaction between the spike's heptad repeat (HR) regions 1 (HR1) and 2 (HR2) crucial step during process these conserved HR constitute attractive targets for inhibitors. However, relative importance each subregion long HR1-HR2 interface viral inhibition remains unclear. Here, we designed, produced, characterized series chimeric miniproteins that mimic two different half subdomains HR1. proteins were designed as single polypeptide chains spontaneously fold into antiparallel trimeric helical bundles aimed at structurally imitate molecular surface HR1 subregion. All folded stably structures could bind complementary HR2 peptides with moderate affinity. only mimicking N-terminal subdomain, but not those imitating C-terminal one, inhibit cell infection by SARS-COV-2 real viruses in cultures. Most interestingly, inhibitory activity correlated their structural stability, binding affinity peptides. These results are relevant designing more focused active inhibitors targeting region Spike.
Language: Английский
Citations
1