Abstract
Peptides can be used as research tools and for diagnostic or therapeutic applications. Peptides, alongside small molecules and antibodies, are used and are gaining further interest as protein-protein interaction (PPI) modulators. Peptides have high target specificity and high affinity, but, unlike small molecule modulators, they are not able to cross the cell membranes to reach their intracellular targets. To overcome this limitation, the special property of the cell-penetrating peptides (CPPs) could benefit their cause. CPPs are a class of peptides that can enter the cells and with them also deliver the attached cargoes. Today, with the advancement of in silico prediction tools and the availability of protein databases, designing new and multifunctional peptides that are able to reach intracellular targets and inhibit certain cellular processes in a very specific manner is reachable. Although there are several efficient CPP sequences already known, the discovery of new CPPs is crucial for the development of efficient delivery methods for both biotechnological and therapeutic applications. In this work, we chose 10 human nuclear proteins from which we predicted new potential CPP sequences by using three different CPP predictors: cell-penetrating peptide prediction tool, CellPPD, and SkipCPP-Pred. From each protein, one predicted CPP sequence was synthesized and its internalization into cells was assessed. Out of the tested sequences, three peptides displayed features characteristic to CPPs. These peptides and also the predicted peptide sequences could be used to design and modify new CPPs. In this work, we show that we can use protein sequences as input for generating new peptides with cell internalization properties. Three new CPPs, AHRR8-24, CASC3251-264, and AKIP127-37, can be further used for the delivery of other cargoes or designed into multifunctional peptides with capability of internalizing cells.
Highlights
There are many macromolecules with high potential in therapeutic and biotechnological applications
We aimed to find new cell-penetrating peptides (CPPs) from human proteins by using different prediction programs followed by the synthesis and assessment of internalization of these peptides
All the predicted CPP sequences that scored higher than 1 were further screened with the online predictors CellPPD and Protein/encoding gene, aliases
Summary
There are many macromolecules with high potential in therapeutic and biotechnological applications Their use is limited due to their inability to efficiently cross cell membranes to reach intracellular targets. One of the chemical methods is the use of CPPs. CPPs are generally defined as 4–40 amino acid (aa) long peptides that can CPPs Predicted From Proteins enter cells and with them enhance the cellular uptake of associated cargo. The majority of validated CPPs are either synthetic or protein derived (Supplementary Figure S1A). Attachment of fluorophore to the CPP sequence is often used to confirm the cell penetration ability (Supplementary Figure S1B), different cargoes, such as nucleic acids, proteins, and PNAs, are possible. Peptide sequences or other cargo can be attached to mediate other bio functions, such as PPI modulation and cell proliferation
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