SARS-CoV-2 Cyclic Peptides

The sialic acid binding site is a promising SARS-CoV-2 therapeutic target. Its large and flat binding site is suitable for designing cyclic peptides that would bind like protein-protein interactions (PPI).

Two-thirds of the clinically approved peptides are cyclic ones. Cyclic peptides have a larger surface area and rigid structures compared to small molecules and linear peptides, respectively. Their rigidity enhances the binding affinity and reduces the non-specific binding. However, it is very difficult to synthesize them using ordinary cyclic reactions, and their yield is mostly low. Also, their intrinsic poor cellular permeability and difficulties in their computational design make their development challenging.

In this work, we plan to design and synthesize modified anti-SARS-CoV-2 cyclic peptides that target the sialic acid binding site. The peptides will be synthesized using SPPS and cyclized using different chemical and/or chemoenzymatic approaches. We will also try to improve their pharmacokinetic properties using different approaches such as prenylation, glycosylation, and/or PEGylation. Then, they will be tested for their antiviral activity. This work aims to design and chemically synthesize modified cyclic peptides with high binding affinity and specificity toward the sialic acid binding site of SARS-CoV-2. Molecular docking has been performed by scanning a library of cyclic peptides. Compounds with the lowest binding affinity will be synthesized, and their SARS-CoV-2 activity will be tested. Then, we will move further to optimize them through different ways (Figure 1).