Novel Lung Targeting Cell Penetrating Peptides as Vectors for Delivery of Therapeutics

Abstract

Cell penetrating peptides are unique, 5-30 amino acid long peptides that are able to breach cell membrane barriers and carry cargoes intracellularly in a functional form. Our prior work identified a synthetic, non-naturally occurring 12-amino acid long peptide that we termed cardiac targeting peptide (CTP: APWHLSSQYSRT) due to its ability to transduce cardiomyocytes in vivo. Studies looking into its mechanism of transduction identified two lung targeting peptides (LTPs), S7A (APWHLSAQYSRT) and R11A (APWHLSSQYSAT). These peptides robustly transduced human bronchial epithelial cell lines in vitro and mouse lung tissue in vivo. This uptake occurred independently of clathrin mediated endocytosis. Biodistribution studies of R11A showed peak uptake at 15 minutes with uptake in liver but not kidneys, indicating primarily a hepatobiliary mode of excretion. Cyclic version of both peptides was ~100-fold more efficient in permeating cells than their linear counterparts. As proof of principle, we conjugated anti-spike and anti-envelope SARS-CoV-2 siRNAs to cyclized R11A and demonstrate anti-viral efficacy in vitro. Our work presented here identifies two novel lung-specific cell penetrating peptides that could potentially deliver myriad therapeutic cargoes to lung tissue.

Tissue-Specific Cell Penetrating Peptides for Targeted Delivery of Small Interfering RNAs

“…The same peptide/siRNA complex has also shown promising results in vivo in inflammation-based pathologies such as contact dermatitis 127 and rheumatoid arthritis 128 . Finally, a CPP called lung targeting peptide was shown to be effective at delivering siRNA against SARS-CoV2 when anti-spike siRNA was attached to a cyclic version of the lung targeting peptide, demonstrating anti-viral efficacy in vitro 129 . More work is needed to confirm these findings; however, a simple inhaled CPP/siRNAbased treatment for SARS-CoV2 would be extremely advantageous in today's day and age.…”