Synthetic molecular evolution of hybrid cell penetrating peptides.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29967329.
- Also identified by DOI 10.1038/s41467-018-04874-6 and PMC identifier 6028423.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 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 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.
Medical subject headings
- Cell-Penetrating Peptides
- Directed Molecular Evolution
- Drug Delivery Systems
- Gain of Function Mutation
- Peptide Nucleic Acids