tetano
Editor, Senior Moderator
Sci Rep
. 2025 Jul 31;15(1):28039.
doi: 10.1038/s41598-025-12444-2. Fusion of SARS-CoV-2 neutralizing LCB1 peptide with Bacillus amyloliquefaciens RNase improves antiviral efficacy
Nikita N Kostin[SUP] 1 [/SUP], Tatyana V Bobik[SUP] 1 [/SUP], Elena V Konovalova[SUP] 1 [/SUP], Milita V Kocharovskaya[SUP] 1 [/SUP], Maria A Simonova[SUP] 1 [/SUP], Natalia Yu Rushkevich[SUP] 1 [/SUP], Yuliana A Mokrushina[SUP] 1 [/SUP], George A Skryabin[SUP] 1 [/SUP], Roman S Kalinin[SUP] 2 [/SUP], Sergey I Kovalchuk[SUP] 1 [/SUP], Rustam H Ziganshin[SUP] 1 [/SUP], Leonid A Kaluzhskiy[SUP] 3 [/SUP], Oksana V Gnedenko[SUP] 3 [/SUP], Evgeniy O Yablokov[SUP] 3 [/SUP], Alexis S Ivanov[SUP] 3 [/SUP], Aleksandr S Chernov[SUP] 1 [/SUP], Vitaly A Kazakov[SUP] 1 [/SUP], Oksana N Khokhlova[SUP] 1 [/SUP], Arkady N Murashev[SUP] 1 [/SUP], Senlian Hong[SUP] 4 [/SUP], Elena I Shramova[SUP] 1 [/SUP], Alexey A Schulga[SUP] 1 [/SUP], Ekaterina N Lyukmanova[SUP] 1 5 [/SUP], Mikhail P Kirpichnikov[SUP] 1 6 [/SUP], Ivan V Smirnov[SUP] 1 [/SUP], Alexey A Belogurov[SUP] 1 [/SUP], Yuri P Rubtsov[SUP] 1 [/SUP], Alexey V Stepanov[SUP] 7 [/SUP], Hongkai Zhang[SUP] 8 [/SUP], Alexander G Gabibov[SUP] 9 10 [/SUP], Sergey M Deyev[SUP] 11 [/SUP]
Affiliations
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 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 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.
Keywords: Antiviral peptide; Barnase; Half-life extension; Pharmacokinetics; SARS-CoV-2; Virus neutralizing peptides (VNPs).
. 2025 Jul 31;15(1):28039.
doi: 10.1038/s41598-025-12444-2. Fusion of SARS-CoV-2 neutralizing LCB1 peptide with Bacillus amyloliquefaciens RNase improves antiviral efficacy
Nikita N Kostin[SUP] 1 [/SUP], Tatyana V Bobik[SUP] 1 [/SUP], Elena V Konovalova[SUP] 1 [/SUP], Milita V Kocharovskaya[SUP] 1 [/SUP], Maria A Simonova[SUP] 1 [/SUP], Natalia Yu Rushkevich[SUP] 1 [/SUP], Yuliana A Mokrushina[SUP] 1 [/SUP], George A Skryabin[SUP] 1 [/SUP], Roman S Kalinin[SUP] 2 [/SUP], Sergey I Kovalchuk[SUP] 1 [/SUP], Rustam H Ziganshin[SUP] 1 [/SUP], Leonid A Kaluzhskiy[SUP] 3 [/SUP], Oksana V Gnedenko[SUP] 3 [/SUP], Evgeniy O Yablokov[SUP] 3 [/SUP], Alexis S Ivanov[SUP] 3 [/SUP], Aleksandr S Chernov[SUP] 1 [/SUP], Vitaly A Kazakov[SUP] 1 [/SUP], Oksana N Khokhlova[SUP] 1 [/SUP], Arkady N Murashev[SUP] 1 [/SUP], Senlian Hong[SUP] 4 [/SUP], Elena I Shramova[SUP] 1 [/SUP], Alexey A Schulga[SUP] 1 [/SUP], Ekaterina N Lyukmanova[SUP] 1 5 [/SUP], Mikhail P Kirpichnikov[SUP] 1 6 [/SUP], Ivan V Smirnov[SUP] 1 [/SUP], Alexey A Belogurov[SUP] 1 [/SUP], Yuri P Rubtsov[SUP] 1 [/SUP], Alexey V Stepanov[SUP] 7 [/SUP], Hongkai Zhang[SUP] 8 [/SUP], Alexander G Gabibov[SUP] 9 10 [/SUP], Sergey M Deyev[SUP] 11 [/SUP]
Affiliations
- PMID: 40744985
- DOI: 10.1038/s41598-025-12444-2
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 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 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.
Keywords: Antiviral peptide; Barnase; Half-life extension; Pharmacokinetics; SARS-CoV-2; Virus neutralizing peptides (VNPs).