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<p>Virus-neutralizing peptides (VNPs) emerged as promising antiviral drug candidates with unprecedented specificity and cost-effectiveness during the recent COVID-19 pandemic. However, limited avidity, lack of effector functions, short circulatory half-life, and restricted administration routes make them inferior compared to neutralizing antibodies. To address these constraints, a potent VNP that targets the SARS-CoV-2&#xa0;S protein is combined with Barnase, a highly active RNA-cleaving enzyme from <i>Bacillus amyloliquefaciens</i>. The resulting LCB1-Barnase (LCB1-Bn) chimera retains strong binding affinity for the SARS-CoV-2&#xa0;S protein and demonstrates a fourfold reduction in IC<sub>50</sub> compared to the LCB1 peptide alone in competitive ELISA and in in vitro neutralization tests. In transgenic CAG-hACE2 mice infected with wild-type SARS-CoV-2, intranasal administration of LCB1-Bn significantly improves survival and reduces viral load by 29-fold. To extend circulation life and allow systemic intravenous administration, an albumin-binding domain (ABD) from <i>Streptococcus</i> protein G is added to LCB1-Bn, producing LCB1-ABD-Bn fusion protein which displays a 95-fold increase in serum half-life. LCB1-ABD-Bn exhibits good tolerability at doses below 10&#xa0;mg/kg and provides protection of SARS-CoV-2-infected CAG-hACE2 animals in 24-hour post-infection intraperitoneal treatment. Cryo-EM reveals the LCB1-ABD-Bn’s tight interaction with S protein RBD domains, highlighting its potential as a promising drug candidate against SARS-CoV-2.</p>

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Fusion of SARS-CoV-2 neutralizing LCB1 peptide with Bacillus amyloliquefaciens RNase improves antiviral efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Nikita N. Kostin,
  • Tatyana V. Bobik,
  • Elena V. Konovalova,
  • Milita V. Kocharovskaya,
  • Maria A. Simonova,
  • Natalia Yu Rushkevich,
  • Yuliana A. Mokrushina,
  • George A. Skryabin,
  • Roman S. Kalinin,
  • Sergey I. Kovalchuk,
  • Rustam H. Ziganshin,
  • Leonid A. Kaluzhskiy,
  • Oksana V. Gnedenko,
  • Evgeniy O. Yablokov,
  • Alexis S. Ivanov,
  • Aleksandr S. Chernov,
  • Vitaly A. Kazakov,
  • Oksana N. Khokhlova,
  • Arkady N. Murashev,
  • Senlian Hong,
  • Elena I. Shramova,
  • Alexey A. Schulga,
  • Ekaterina N. Lyukmanova,
  • Mikhail P. Kirpichnikov,
  • Ivan V. Smirnov,
  • Alexey A. Belogurov,
  • Yuri P. Rubtsov,
  • Alexey V. Stepanov,
  • Hongkai Zhang,
  • Alexander G. Gabibov,
  • Sergey M. Deyev

摘要

Virus-neutralizing peptides (VNPs) emerged as promising antiviral drug candidates with unprecedented specificity and cost-effectiveness during the recent COVID-19 pandemic. However, limited avidity, lack of effector functions, short circulatory half-life, and restricted administration routes make them inferior compared to neutralizing antibodies. To address these constraints, a potent VNP that targets the SARS-CoV-2 S protein is combined with Barnase, a highly active RNA-cleaving enzyme from Bacillus amyloliquefaciens. The resulting LCB1-Barnase (LCB1-Bn) chimera retains strong binding affinity for the SARS-CoV-2 S protein and demonstrates a fourfold reduction in IC50 compared to the LCB1 peptide alone in competitive ELISA and in in vitro neutralization tests. In transgenic CAG-hACE2 mice infected with wild-type SARS-CoV-2, intranasal administration of LCB1-Bn significantly improves survival and reduces viral load by 29-fold. To extend circulation life and allow systemic intravenous administration, an albumin-binding domain (ABD) from Streptococcus protein G is added to LCB1-Bn, producing LCB1-ABD-Bn fusion protein which displays a 95-fold increase in serum half-life. LCB1-ABD-Bn exhibits good tolerability at doses below 10 mg/kg and provides protection of SARS-CoV-2-infected CAG-hACE2 animals in 24-hour post-infection intraperitoneal treatment. Cryo-EM reveals the LCB1-ABD-Bn’s tight interaction with S protein RBD domains, highlighting its potential as a promising drug candidate against SARS-CoV-2.