Targeting SARS-CoV-2 spike protein by stapled hACE2 peptides

Area of Science:

• Structural biology and medicinal chemistry
• Virology and infectious diseases

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) utilizes its Spike protein's Receptor Binding Domain (RBD) to bind the human Angiotensin-Converting Enzyme 2 (hACE2) receptor.
• This interaction is critical for viral entry into host cells, initiating infection and disease progression.
• Developing inhibitors that block this RBD-hACE2 interaction is a key strategy for anti-COVID-19 therapeutics.

Purpose of the Study:

• To design and synthesize novel lactam-based stapled peptides derived from hACE2.
• To evaluate the efficacy of these stapled peptides in inhibiting the interaction between the SARS-CoV-2 Spike protein RBD and the hACE2 receptor.

Main Methods:

• Design and synthesis of lactam-based i,i + 4 stapled peptides based on the hACE2 sequence.
• In vitro screening assays to assess the inhibition of the Spike protein RBD-hACE2 complex formation.
• Determination of inhibitory concentration 50 (IC50) and dissociation constant (Kd) values for effective stapled peptides.

Main Results:

• The stapled peptide hACE2_21-55A36K-F40E demonstrated significant inhibition of the Spike protein RBD-hACE2 complex formation.
• The IC50 value for this peptide was determined to be 3.6 μM, and its Kd was 2.1 μM.
• These results indicate a potent inhibitory effect of the stapled peptide on the viral binding interface.

Conclusions:

• Lactam-based stapled peptides derived from hACE2 are effective inhibitors of SARS-CoV-2 Spike protein binding.
• The hACE2_21-55A36K-F40E stapled peptide represents a promising lead compound for developing new anti-COVID-19 therapeutics.
• hACE2 peptidomimetics offer a viable strategy for blocking viral entry and combating SARS-CoV-2 infection.