Abstract
Cell-penetrating peptides (CPPs) have distinct properties to translocate across cell envelope. The key property of CPPs to translocation with attached molecules has been utilized as vehicles for the delivery of several potential drug candidates that illustrate the significant effect in in-vitro experiment but fail in in-vivo experiment due to selectively permeable nature of cell envelop. Penetratin, a well-known CPP identified from the third α-helix of Antennapedia homeodomain of Drosophila, has been widely used and studied for the delivery of bioactive molecules to treat cancers, stroke, and infections caused by pathogenic organisms. Few studies have demonstrated that penetratin directly possesses antimicrobial activities against bacterial and fungal pathogens; however, the mechanism is unknown. In this study, we have utilized the power of high-throughput Saccharomyces cerevisiae proteome microarrays to screen all the potential protein targets of penetratin. Saccharomyces cerevisiae proteome microarrays assays of penetratin followed by statistical analysis depicted 123 Saccharomyces cerevisiae proteins as the protein targets of penetratin out of ~5800 Saccharomyces cerevisiae proteins. To understand the target patterns of penetratin, enrichment analyses were conducted using 123 protein targets. In biological process: ribonucleoprotein complex biogenesis, nucleic acid metabolic process, actin filament-based process, transcription, DNA-templated, and negative regulation of gene expression are a few significantly enriched terms. Cytoplasm, nucleus, and cell-organelles are enriched terms for cellular component. Protein-protein interactions network depicted ribonucleoprotein complex biogenesis, cortical cytoskeleton, and histone binding, which represent the major enriched terms for the 123 protein targets of penetratin. We also compared the protein targets of penetratin and intracellular protein targets of antifungal AMPs (Lfcin B, Histatin-5, and Sub-5). The comparison results showed few unique proteins between penetratin and AMPs. Nucleic acid metabolic process and cellular component disassembly were the common enrichment terms for penetratin and three AMPs. Penetratin shows unique enrichment items that are related to DNA biological process. Moreover, motif enrichment analysis depicted different enriched motifs in the protein targets of penetratin, LfcinB, Histatin-5, and Sub-5.
Highlights
Anti-microbial peptides (AMPs), produced throughout the living organisms, provide the first line of rapid defense against invading pathogens [1]
AMPs are categorized into two major classes: one that targets membrane and the other that penetrate across membranes without disrupting membrane [8]
Data from triplicate yeast proteome microarrays assays of penetratin were statistically analyzed following cutoff parameters to identify the protein targets of penetratin. These identified protein targets were subjected to several bioinformatics tools, like PANTHER, DAVID, REVIGO, STRING, and STREME databases to understand the binding paptrtoetrenomthermouicgrhoaprrraoytseainssacylassosfifipceanteitorant,inewnreircehsmtaetinstticianllygeanealyoznetdolfolgloyw, pinrgotceuitno–ffppraortaeminetienrsteraction nettowidoernkt,ifayntdheenprroictheiendtamrgoettisf.of penetratin
Summary
Anti-microbial peptides (AMPs), produced throughout the living organisms, provide the first line of rapid defense against invading pathogens [1]. AMPs are positively charged short peptides (usually >50 residues) with a wide range of antimicrobial activities against pathogenic bacteria, fungi, viruses, and even cancer cells [2,3]. The intracellular targeting AMPs with the ability to cross membrane are studied as transport vectors to deliver the bioactive substances inside the cells [9,10]. Cell-penetrating peptides (CPPs) are small cationic peptides with membrane translocation ability widely used for the internalization of attached cargo molecules [11,12,13]. Biological and biophysical studies on penetratin have provided meaningful insight into translocation, cargo delivery and antimicrobial activities, the antimicrobial mechanism of action and the target are unclear. A comparative study was performed to understand the mechanism of penetratin and antifungal AMPs
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