Antiviral Activity against SARS-CoV-2 of Conformationally Constrained Helical Peptides Derived from Angiotensin-Converting Enzyme 2

Abstract

Despite the availability of vaccines, COVID-19 continues to be aggressive, especially in immunocompromised individuals. Therefore, the development of a specific therapeutic agent with antiviral activity against SARS-CoV-2 is necessary. The infection pathway starts when the receptor binding domain of the viral spike protein interacts with the angiotensin converting enzyme 2 (ACE2), which acts as a host receptor for the RBD expressed on the host cell surface. In this scenario, ACE2 analogs binding to the RBD and preventing the cell entry can be promising antiviral agents. Most of the ACE2 residues involved in the interaction belong to the α1 helix, more specifically to the minimal fragment ACE2(24−42). In order to increase the stability of the secondary structure and thus antiviral activity, we designed different triazole-stapled analogs, changing the position and the number of bridges. The peptide called P3, which has the triazole-containing bridge in the positions 36−40, showed promising antiviral activity at micromolar concentrations assessed by plaque reduction assay. On the other hand, the double-stapled peptide P4 lost the activity, showing that excessive rigidity disfavors the interaction with the RBD.

Comparative Analysis of Cyclization Techniques in Stapled Peptides: Structural Insights into Protein–Protein Interactions in a SARS-CoV-2 Spike RBD/hACE2 Model System

“…Surprisingly, the hydrocarbon staple peptide 11 demonstrated a significantly higher inhibition efficacy than peptide 4 , which suggests that an excessive level of rigidity may be detrimental to its antiviral activity. In fact, a recent study demonstrated significantly superior antiviral activity of single-stapled peptides compared with their less-flexible, double-stapled analogues [ 21 ].…”

“…Several independent research groups have focused on peptidomimetic synthesis based on the α1-helix of hACE2. They have produced peptides ranging from 9–65 residues, and their work has highlighted the direct impact of helicity on antiviral activity [ 18 , 19 , 20 , 21 , 22 , 23 ]. However, a systematic comparative study of the i , i + 4 helix-inducing constraints leading to the desired hACE2 α-helical conformation has not been conducted to date.…”

Chemically modified antiviral peptides against SARS‐CoV‐2

“…[65][66][67][68] We used this approach to perform a structure-activity relationship with mono-and ditriazolyl bridged peptides derived from the minimal sequence ACE2(24-42). 57 In particular, the analog clicked at position 36-40 features a more stable secondary structure and increased antiviral activity as compared to the native fragment (Entry 4, Table 1).…”

The Role of the Unbinding Cycle on the Coordination Abilities of the Bi-Cyclopeptides toward Cu(II) Ions

“…The presence of a second cycle results in an even greater increase in biological stability and ability to bind to the receptor, as each ring in the bicyclic structure can function independently, which makes these peptides bifunctional [21]. Thus, bicyclic peptides offer high expectations for the development of new drug candidates carriersdue to their structural similarity with proteins [22].…”