The outbreak caused by SARS-CoV-2 has taken many lives worldwide. Although vaccination has started, the development of drugs to either alleviate or abolish symptoms of COVID-19 is still necessary. Here, four synthetic peptides were assayed regarding their ability to protect Vero E6 cells from SARS-CoV-2 infection and their toxicity to human cells and zebrafish embryos. All peptides had some ability to protect cells from infection by SARS-CoV-2 with the D614G mutation. Molecular docking predicted the ability of all peptides to interact with and induce conformational alterations in the spike protein containing the D614G mutation. PepKAA was the most effective peptide, by having the highest docking score regarding the spike protein and reducing the SARS-CoV-2 plaque number by 50% (EC50) at a concentration of 0.15 mg mL–1. Additionally, all peptides had no toxicity to three lines of human cells as well as to zebrafish larvae and embryos. Thus, these peptides have potential activity against SARS-CoV-2, making them promising to develop new drugs to inhibit cell infection by SARS-CoV-2.

Neutralizing Effect of Synthetic Peptides toward SARS-CoV-2

The angiotensin-converting enzyme 2 (ACE2) is the receptor used by SARS-CoV and SARS-CoV-2 coronaviruses to attach to cells via the receptor-binding domain (RBD) of their viral spike protein. Since the start of the COVID-19 pandemic, several structures of protein complexes involving ACE2 and RBD as well as monoclonal antibodies and nanobodies have become available. We have leveraged the structural data to design peptides to target the interaction between the RBD of SARS-CoV-2 and ACE2 and SARS-CoV and ACE2, as contrasting exemplar, as well as the dimerization surface of ACE2 monomers. The peptides were modelled using our original method: PiPreD that uses native elements of the interaction between the targeted protein and cognate partner(s) that are subsequently included in the designed peptides. These peptides recapitulate stretches of residues present in the native interface plus novel and highly diverse conformations surrogating key interactions at the interface. To facilitate the access to this information we have created a freely available and dedicated web-based repository, PepI-Covid19 database, providing convenient access to this wealth of information to the scientific community with the view of maximizing its potential impact in the development of novel therapeutic and diagnostic agents.

A Collection of Designed Peptides to Target SARS-CoV-2 Spike RBD-ACE2 Interaction.

The global concern over emerging and re-emerging viral infections has spurred the search for novel antiviral agents. Peptides with antiviral activity stand out, by overcoming limitations of the current drugs utilized, due to their biocompatibility, specificity and effectiveness. Synthetic peptides have been shown to be viable alternatives to natural peptides due to several difficulties of using of the latter in clinical trials. Various platforms have been utilized by researchers to predict the most effective peptide sequences against HIV, influenza, dengue, MERS and SARS. Synthetic peptides are already employed in the treatment of HIV infection. The novelty of this study is to discuss, for the first time, the potential of synthetic peptides as antiviral molecules. We conclude that synthetic peptides can act as new weapons against viral threats to humans.

Synthetic antiviral peptides: a new way to develop targeted antiviral drugs

Cancer patients who receive radiotherapy have a high risk of severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) infection, but the concrete reason remains unclear. Herein, we investigated the influence of irradiation on the vulnerability of cancer cells to SARS‐CoV‐2 using S pseudovirions and probed the underlying mechanism via RNA‐seq and other molecular biology techniques. Owing to the enhancement of sphingolipid metabolism, irradiation accelerated pseudovirion infection. Mechanistically, irradiation induced the expression of acid sphingomyelinase (ASM), which catalyses the hydrolysis of sphingomyelin to ceramide, contributing to lipid raft formation and promoting SARS‐CoV‐2 invasion. Inhibition of lipid raft formation with methyl‐β‐cyclodextrin (MβCD) or the tyrosine kinase inhibitor genistein and ASM suppression through small interfering RNA or amitriptyline (AMT) treatment abolished the enhancing effect of irradiation on viral infection. Animal experiments supported the finding that irradiation promoted SARS‐CoV‐2 S pseudovirion infection in A549 cell tumour‐bearing BALB/c nude mice, whereas AMT treatment dramatically decreased viral infection. This study discloses the role of sphingolipid metabolism in irradiation‐induced SARS‐CoV‐2 infection, thus providing a potential target for clinical intervention to protect patients receiving radiotherapy from COVID‐19.

Irradiation accelerates SARS‐CoV‐2 infection by enhancing sphingolipid metabolism

Abstract The pathogenic agent of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters into human cells through the interaction between the receptor binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor. Efforts have been made towards finding antivirals that block this interaction, therefore preventing infection. Here, we determined the binding affinity of ACE2-derived peptides to the RBD of SARS-CoV-2 experimentally and performed MD simulations in order to understand key characteristics of their interaction. One of the peptides, p6, binds to the RBD of SARS-CoV-2 with nM affinity. Although the ACE2-derived peptides retain conformational flexibility when bound to SARS-CoV-2 RBD, we identified residues T27 and K353 as critical anchors mediating the interaction. New ACE2-derived peptides were developed based on the p6-RBD interface analysis and expecting the native conformation of the ACE2 to be maintained. Furthermore, we found a correlation between the helicity in trifluoroethanol and the binding affinity to RBD of the new peptides. Under the hypothesis that the conservation of peptide secondary structure is decisive to the binding affinity, we developed a cyclized version of p6 which had more helicity than p6 and approximately half of its K D value.

Zhuanzhuan Wei

Papers

An angiotensin-converting enzyme-2-derived heptapeptide GK-7 for SARS-CoV-2 spike blockade.

Irradiation accelerates SARS‐CoV‐2 infection by enhancing sphingolipid metabolism