“…These findings suggest that either S-20-1 or 5-Helix could be further developed for therapeutic or prophylactic use, either alone or in combination with EK1, to treat or prevent infection by SARS-CoV-2 and its variants. Additionally, several other SARS-CoV-2 HR1-targeting inhibitors, such as HY3000 and YKYY017 that may be derived from P3 peptide [ 29 ] and IPB24 peptide [ 30 ], respectively, are being developed in clinical or preclinical trials. Figure 3.…”
Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number of infections, reinfections, and vaccine-breakthrough infections, seriously threatening human health. Recently, several new Omicron subvariants, such as BA.5, BA.2.75, BA.4.6, and BF.7, bearing distinct mutation profiles in their spike (S) proteins, have significantly increased their capacity to evade vaccine-induced immunity and have shown enhanced infectivity and transmissibility, quickly becoming dominant sublineages. In this study, we found the S proteins of these Omicron subvariants to have 2- to 4-fold more efficient membrane fusion kinetics than that of the original Omicron variant (BA.1), indicating that these novel Omicron subvariants might possess increased pathogenicity. We also identified that peptide-based pan-CoV fusion inhibitors, EK1 and EK1C4, showed equal efficacy against membrane fusion mediated by S proteins of the noted Omicron subvariants and infection by their pseudoviruses. Additionally, either immune sera induced by wild-type (WT) SARS-CoV-2 RBD-based vaccine or BA.2 convalescent sera showed potent synergism with EK1 against both WT SARS-CoV-2 and various Omicron subvariants, further suggesting that EK1-based fusion inhibitors are promising candidates for development as clinical antiviral agents against the currently circulating Omicron subvariants.
“…These findings suggest that either S-20-1 or 5-Helix could be further developed for therapeutic or prophylactic use, either alone or in combination with EK1, to treat or prevent infection by SARS-CoV-2 and its variants. Additionally, several other SARS-CoV-2 HR1-targeting inhibitors, such as HY3000 and YKYY017 that may be derived from P3 peptide [ 29 ] and IPB24 peptide [ 30 ], respectively, are being developed in clinical or preclinical trials. Figure 3.…”
Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number of infections, reinfections, and vaccine-breakthrough infections, seriously threatening human health. Recently, several new Omicron subvariants, such as BA.5, BA.2.75, BA.4.6, and BF.7, bearing distinct mutation profiles in their spike (S) proteins, have significantly increased their capacity to evade vaccine-induced immunity and have shown enhanced infectivity and transmissibility, quickly becoming dominant sublineages. In this study, we found the S proteins of these Omicron subvariants to have 2- to 4-fold more efficient membrane fusion kinetics than that of the original Omicron variant (BA.1), indicating that these novel Omicron subvariants might possess increased pathogenicity. We also identified that peptide-based pan-CoV fusion inhibitors, EK1 and EK1C4, showed equal efficacy against membrane fusion mediated by S proteins of the noted Omicron subvariants and infection by their pseudoviruses. Additionally, either immune sera induced by wild-type (WT) SARS-CoV-2 RBD-based vaccine or BA.2 convalescent sera showed potent synergism with EK1 against both WT SARS-CoV-2 and various Omicron subvariants, further suggesting that EK1-based fusion inhibitors are promising candidates for development as clinical antiviral agents against the currently circulating Omicron subvariants.
“…The expression profiles of the S proteins with HR2 mutations in transfected cells or PsV particles were examined by western blotting as described previously ( Zhu et al, 2022b ). In brief, 5 × 10 5 /ml 293T cells were seeded in a 6-well plate and transfected by an S-expressing plasmid.…”
Section: Methodsmentioning
confidence: 99%
“…The S-mediated cell-cell fusion was also measured by a dual-split-protein (DSP)-based cell-cell fusion assay ( Zhu et al, 2022b ). 1.5 × 10 4 293T cells were seeded in a 96-well plate as effector cells, 1.5 × 10 5 /ml of 293T/ACE2, Huh-7 or Vero E6 cells were cultured in a 10-cm culture dish as target cells.…”
Section: Methodsmentioning
confidence: 99%
“…Infectivity of various SARS-CoV-2 pseudoviruses (PsV) in 293T/ACE2 or Huh-7 as target cells was determined by a single-cycle infection assay as described previously ( Zhu et al, 2022b ). To package a PsV, 5 × 10 6 293T cells grown in 15 ml of growth medium in a T-75 culture flask were cotransfected with the S-expressing plasmids and a lentiviral backbone plasmid (pNL4-3.…”
Section: Methodsmentioning
confidence: 99%
“…In the past decade, we have devoted to develop HIV fusion inhibitors, with Sifuvirtide and Lipovirtide under clinical trials ( Chong et al, 2019 ; He et al, 2008a , 2008b ; Xue et al, 2022 ). After SARS-CoV-2 outbreak, we immediately initiated projects to develop antivirals, generating a group of fusion-inhibitory peptides and lipopeptides with very potent and broad-spectrum activities ( Yu et al, 2021a , 2021b ; Zhu et al, 2020 , 2021 , 2022a , 2022b ). As illustrated in Fig.…”
Development of potent and broad‐spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains one of the top priorities, especially in the cases of the emergence of mutant viruses and inability of 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, we report its design strategy and preclinical data. First, we surprisingly found that IPB29 with a rigid linker between the peptide sequence and lipid molecule had greatly improved α‐helical structure and antiviral activity. Second, IPB29 potently inhibited a large panel of SARS‐CoV‐2 variants including the previously and currently circulating viruses, such as Omicron XBB.5.1 and EG.5.1. Third, IPB29 could also cross‐neutralize the bat‐ and pangolin‐isolated SARS‐CoV‐2‐related CoVs (RatG13, PCoV‐GD, and PCoV‐GX) and other human CoVs (SARS‐CoV, MERS‐CoV, HCoV‐NL63, and HCoV‐229E). Fourth, IPB29 administrated as an inhalation solution (IPB29‐IS) in Syrian hamsters exhibited high therapeutic and preventive efficacies against SARS‐CoV‐2 Delta or Omicron variant. Fifth, the pharmacokinetic profiles and safety pharmacology of IPB29‐IS were extensively characterized, providing data to support its evaluation in humans. In conclusion, our studies have demonstrated a novel design strategy for viral fusion inhibitors and offered an ideal drug candidate against SARS‐CoV‐2 and other coronaviruses.
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