Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• The COVID-19 pandemic necessitates ongoing research into effective antiviral therapies.
• Targeting the SARS-CoV-2 spike protein's interaction with the ACE2 receptor is a key strategy for drug development.
• Naturally occurring antibiotics offer structural scaffolds for novel therapeutic agents.

Purpose of the Study:

• To design and synthesize novel peptidomimetics (PMs) based on polymyxin B.
• To target two distinct regions of the SARS-CoV-2 spike protein's receptor-binding domain (RBD).
• To evaluate the binding affinity and antiviral activity of these PMs against SARS-CoV-2.

Main Methods:

• Design and synthesis of polymyxin-based peptidomimetics (monomers and heterodimers).
• Surface plasmon resonance assays to determine binding affinity (K_D) to the S-RBD.
• Cell-based assays using authentic SARS-CoV-2 to assess inhibition of viral entry.

Main Results:

• Synthesized monomers and heterodimers demonstrated micromolar binding affinity to the S-RBD.
• Heterodimers 7 and 10 exhibited K_D values between 2.31 μM and 2.78 μM.
• Dimer 10 showed minimal, detectable inhibition of SARS-CoV-2 entry in cell lines expressing ACE2 and TMPRSS2.

Conclusions:

• The study validates the feasibility of using medium-sized heterodimeric peptidomimetics to target the S-RBD.
• Heterodimers 7 and 10 serve as promising leads for developing optimized polymyxin-related compounds.
• Further optimization could enhance S-RBD affinity and anti-SARS-CoV-2 potential for future drug development.