Synthetic molecular evolution of hybrid cell penetrating peptides

W. Berkeley Kauffman, Shantanu Guha and William C. Wimley ()
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W. Berkeley Kauffman: Tulane University School of Medicine
Shantanu Guha: Tulane University School of Medicine
William C. Wimley: Tulane University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract 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 pTat48–60 (tat) and pAntp43–68 (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.

Date: 2018
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DOI: 10.1038/s41467-018-04874-6

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