Structurally Modified Bioactive Peptide Inhibits SARS-CoV-2 Lentiviral Particles Expression

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, which utilizes the ACE2 receptor for cell entry.
• Drug repurposing is a viable strategy for developing COVID-19 therapeutics.
• Ile-Arg-Trp (IRW) is a bioactive tripeptide known to enhance ACE2 expression.

Purpose of the Study:

• To synthesize and evaluate novel IRW analogs for their ability to inhibit the interaction between the SARS-CoV-2 spike protein receptor-binding domain (RBD) and ACE2.
• To assess the therapeutic potential of these analogs in blocking viral entry and replication.

Main Methods:

• Synthesis of IRW analogs A9 (Acetyl-Ile-Arg-Trp-Amide) and A14 (Formyl-Ile-Arg-Trp-Amide).
• In vitro assays to measure inhibition of SARS-CoV-2 S RBD-ACE2 interaction and furin enzymatic activity.
• Cell-based assays using SARS-CoV-2 spike protein and pseudotyped lentiviral particles.
• Computational methods including MMGBSA and molecular dynamics (MD) calculations.

Main Results:

• A9 and A14 significantly reduced SARS-CoV-2 S RBD-ACE2 interaction in vitro.
• Binding free energy calculations indicated favorable interactions of A9 and A14 with the SARS-CoV-2 S RBD.
• A14 demonstrated inhibition of furin enzymatic activity.
• Both analogs decreased SARS-CoV-2 spike protein expression in cells and inhibited viral entry in pseudotyped viral particle assays.

Conclusions:

• Novel IRW analogs, A9 and A14, were successfully synthesized and demonstrated efficacy in inhibiting SARS-CoV-2 host cell binding.
• These findings support the potential of A9 and A14 as lead compounds for developing new antiviral therapies against SARS-CoV-2.