Peptide-based inhibitors hold great promise as the broad-spectrum agents against coronavirus

Abstract

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome (MERS), and the recent SARS-CoV-2 are lethal coronaviruses (CoVs) that have caused dreadful epidemic or pandemic in a large region or globally. Infections of human respiratory systems and other important organs by these pathogenic viruses often results in high rates of morbidity and mortality. Efficient anti-viral drugs are needed. Herein, we firstly take SARS-CoV-2 as an example to present the molecular mechanism of CoV infection cycle, including the receptor binding, viral entry, intracellular replication, virion assembly, and release. Then according to their mode of action, we provide a summary of anti-viral peptides that have been reported in peer-reviewed publications. Even though CoVs can rapidly evolve to gain resistance to the conventional small molecule drugs, peptide-based inhibitors targeting various steps of CoV lifecycle remain a promising approach. Peptides can be continuously modified to improve their antiviral efficacy and spectrum along with the emergence of new viral variants.

SARS-CoV-2 inhibitory activity of a short peptide derived from internal fusion peptide of S2 subunit of spike glycoprotein

“…To date the study of the structure-activity relationship for SARS-CoV-2 S2 peptides derived from the HR2 region demonstrated that an α-helix structure plays a dominant role to block formation of the HR1-HR2 6-helix bundle thus interfering with the virus-host membrane fusion ( Heydari et al., 2021 ; Tang et al., 2023 ). The localization of our PN19 peptide and its ability to bind MPER derived peptide could indicate a different mechanism of inhibitory activity.…”

“…Development of entry and fusion powerful inhibitory peptide have recently increased the clinical interest for their use in treatment of SARS-CoV-2 infection ( Heydari et al., 2021 ). In this context, new small compounds targeting membrane envelope viral structure, as inhibitors of viral entry, can be of value ( Tang et al., 2023 ). A peculiar aspect of the present study is the small size of some S2 SARS-CoV-2 inhibitory peptides studied.…”

“…The S2 subunit is composed of fusion peptide (FP) and internal fusion peptide (IFP) regions, heptad repeat regions 1 and 2 (HR1-2), membrane proximal external region (MPER), transmembrane region (TM), and cytoplasmic tail ( Jackson et al., 2022 ). For their molecular structures and role played during viral cell-fusion, HR1 and HR2 have been used as the targets of many studies based on peptides ( Heydari et al., 2021 ; Tang et al., 2023 ; Mousavi et al., 2023 ). Mechanistically, peptides have been designed to mimic either HR1 or HR2 in the S2 subunit, in order to block formation of the HR1-HR2 6-helix bundle and thus interfering with the virus-host membrane fusion ( Liu et al., 2004 ; Bosch et al., 2004 ).…”

Research Progress on Spike-Dependent SARS-CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike

“…Navitoclax has also been demonstrated to exhibit broad-spectrum activity against a range of VOCs but also retains some activity against SARS-CoV, MERS-CoV, and HCoV-299E [62]. Numerous studies of both peptides and small molecules that target disrupting the 6HB have demonstrated promising broadspectrum activity against sequence variants or more distantly related coronaviruses [63,64]. These results highlight the advantages of targeting the HR1/HR2 assembly of the 6HB postfusion core.…”

High throughput screening identifies broad-spectrum Coronavirus entry inhibitors

“…Strategies to inhibit host proteases like Transmembrane protease serine 2 (TMPRSS2) [17][18][19] and Cathepsins 20,21 , which facilitate CoV entry by cleaving the S protein and activating the fusogenic activity of the S2 domain, have also been explored. Protease inhibitors like Nafamostat 22 and Camostat 19 have demonstrated some efficacy against multiple CoVs 23,24 . However, their inhibition spectrum remains uncertain due to the adaptability of CoVs in exploring alternative proteases 25 , and their evolution to include a polybasic furin cleavage site 26,27 , thereby limiting the strategy of targeting a single protease for broad-spectrum inhibition.…”