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Synthetic molecular evolution of hybrid cell penetrating peptides.


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.

SUBMITTER: Kauffman WB 

PROVIDER: S-EPMC6028423 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Synthetic molecular evolution of hybrid cell penetrating peptides.

Kauffman W Berkeley WB   Guha Shantanu S   Wimley William C WC  

Nature communications 20180702 1


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<sub>48-60</sub> (tat) and pAntp<sub>43-68</sub> (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 d  ...[more]

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