Decoding the proteome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for cell-penetrating peptides involved in pathogenesis or applicable as drug delivery vectors

Abstract

Synthetic or natural derived cell-penetrating peptides (CPPs) are vastly investigated as tools for the intracellular delivery of membrane-impermeable molecules. As viruses are intracellular obligate parasites, viral originated CPPs have been considered as suitable intracellular shuttling vectors for cargo transportation. A total of 310 CPPs were identified in the proteome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Screening the proteome of the cause of COVID-19 reveals that SARS-CoV-2 CPPs (SCV2-CPPs) span the regions involved in replication, protein-nucleotide and protein-protein interaction, protein-metal ion interaction, and stabilization of homo/hetero-oligomers. However, to find the most appropriate peptides as drug delivery vectors, one might face several hurdles. Computational analyses showed that 94.3% of the identified SCV2-CPPs are non-toxins, and 38% are neither antigenic nor allergenic. Interestingly, 36.70% of SCV2-CPPs were resistant to all four groups of protease families. Nearly 1/3 of SCV2-CPPs had sufficient inherent or induced helix and sheet conformation leading to increased uptake efficiency. Heliquest lipid-binding discrimination factor revealed that 44.30% of the helical SCV2-CPPs are lipid-binding helices. Although Cys-rich derived CPPs of helicase (NSP13) can potentially fold into a cyclic conformation in endosomes with a higher rate of endosomal release, the most optimal SCV2-CPP candidates as vectors for drug delivery were SCV2-CPP118, SCV2-CPP119, SCV2-CPP122, and SCV2-CPP129 of NSP12 (RdRp). Ten experimentally validated viral-derived CPPs were also used as the positive control to check the scalability and reliability of our protocol in SCV2-CPP retrieval. Some peptides with a cell-penetration ability known as bioactive peptides are adopted as biotherapeutics themselves. Therefore, 59.60%, 29.63%, and 32.32% of SCV2-CPPs were identified as potential antibacterial, antiviral, and antifungals, respectively. While 63.64% of SCV2-CPPs had immuno-modulatory properties, 21.89% were recognized as anti-cancers. Conclusively, the workflow of this study provides a platform for profound screening of viral proteomes as a rich source of biotherapeutics or drug delivery carriers.

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

“…In this respect, SARS-CoV2 virus, the etiological causative of COVID-19, needs to infect animals or humans to replicate, as other viruses, and as a consequence it should have CCPs in its proteome. A recent computational study analyzed the SARS-CoV-2 proteins and identified >300 sequences with potential CPP ability and involved in important processes like protein–protein interactions and homo/hetero-oligomer stabilization [ 82 ]. Further filtering allowed the identification of peptide sequences with no antigenic or allergenic properties and resistant to main groups of proteases.…”

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade

“…Lately, in an interesting study, screening the proteome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disclosed a total of 310 CPPs. Whereas 64% of these CPPs had immuno-modulatory attributes, 22% were identified with anti-cancer properties [ 8 ]. Experimentally, CPPs have demonstrated to be able to deliver small and large bioactive cargos into cells both in vitro and in vivo [ 9 ].…”

Viral 3CLpro as a Target for Antiviral Intervention Using Milk-Derived Bioactive Peptides

“…The 3-chymotrypsin-like viral protease (3CL pro ) is the main protease of SARS-CoV-2 in charge of cleaving the polyproteins into individual functional components (Hilgenfeld 2014). The 3CL pro operates on at least eleven cleavage sites on the larger polyprotein resulting in non-structural proteins 4-16 (Hemmati et al 2020). These non-structural proteins will later assemble into a replication transcription complex crucial to viral replication (Yang et al 2003).…”