Synthetic molecular evolution of hybrid cell penetrating peptides
Peptides and analogs such as peptide nucleic acids (PNA) are promising tools and therapeutics, but the cell membrane remains a barrier to intracellular targets. Conjugation to classical cell penetrating peptides (CPPs) such as pTat 48–60 (tat) and pAntp 43–68 (penetratin) facilitates delivery; howev...
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Veröffentlicht in: | Nature communications 2018-07, Vol.9 (1), p.2568-10, Article 2568 |
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Sprache: | eng |
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Zusammenfassung: | Peptides and analogs such as peptide nucleic acids (PNA) are promising tools and therapeutics, but the cell membrane remains a barrier to intracellular targets. Conjugation to classical cell penetrating peptides (CPPs) such as pTat
48–60
(tat) and pAntp
43–68
(penetratin) facilitates delivery; however, efficiencies are low. Lack of explicit design principles hinders rational improvement. Here, we use synthetic molecular evolution (SME) to identify gain-of-function CPPs with dramatically improved ability to deliver cargoes to cells at low concentration. A CPP library containing 8192 tat/penetratin hybrid peptides coupled to an 18-residue PNA is screened using the HeLa pTRE-LucIVS2 splice correction reporter system. The daughter CPPs identified are one to two orders of magnitude more efficient than the parent sequences at delivery of PNA, and also deliver a dye cargo and an anionic peptide cargo. The significant increase in performance following a single iteration of SME demonstrates the power of this approach to peptide sequence optimization.
Therapeutic peptide nucleic acids can be delivered into cells by conjugation to cell penetrating peptides (CPPs), but efficiency is usually low. Here the authors use synthetic molecular evolution and a luciferase-based library screen to generate new CPPs with improved efficiency and lower toxicity. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-018-04874-6 |