Cell penetrating peptides (CPPs) have great impacts on both fundamental and translational biomedical research due to their ability to transverse the cell membrane and deliver a range of therapeutics and imaging agents into cells. However, traditional CPPs suffer from proteolytic degradation and limited <i>in vivo</i> circulation half-life. Peptide self-assembly offers an effective method to generate peptide-based nanomaterials with improved stability, biological activity and biocompatibility. We present a class of peptide assemblies, termed supramolecular cell penetrating nanofibers (SCPNs), with intrinsic cell penetrating activity. SCPNs are generated through the self-assembly of <i>de novo</i> designed multidomain peptides (MDPs) containing both a b-sheet self-assembling domain that forms nanofibers and an oligo-lysine membrane-binding domain, connected through an oligopeptide-based spacer. We synthesized a library of MDPs by varying the numbers of lysine residues in the membrane binding domain and the composition of amino acids involved in the spacer. The results showed nanofiber self-assembly is favored as the length of the spacer increases, possibly through reduction of the electrostatic repulsion between the oligo-lysine domains. While most MDPs formed nanofibers, their cell penetrating activity varied. Nanofibers with a longer membrane binding domain exhibited higher cell penetrating activity. Alanine in the spacer domain provided higher stability toward b-sheet packing than spacers consisting of glycine. Alanine seems to provide the optimal conformational flexibility for the oligo-lysine membrane binding compared to MDPs with glycine or leucine residues in the spacer. An expanded library is being currently investigated to develop a more comprehensive structure-activity correlation. Given the increasing interests in the design of cell penetrating materials for vaccine development, in particular mRNA-based vaccine delivery, peptide nanofibers with intrinsic cell penetrating activity would be beneficial to the development of peptide-based immuno-and gene therapy.

Modular design and self-assembly of multidomain peptides toward supramolecular cell penetrating nanofibers

ACS Spring Meeting 2021

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