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

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.
Competing Interests: Competing Interests: MZ along with University of Pittsburgh has two patents filed on the use of lung targeting peptides: Lung-specific targeting-peptide (LTP)-mediated delivery of a therapeutic agent for treating pulmonary viral infection, US patent application No. 63/012,330, filing date April 20th, 2020; and Lung-specific targeting-peptide (LTP), composition and uses thereof, US patent application No. 62/984,925, filing date March 4th, 2020. JMB is a paid consultant to MPEG LA, L.L.C., which has a patent family pending on homo-bivalent linker compounds monosubstituted with an oligonucleotide for use in the synthesis of bioconjugates (WO 2016/205410 A2).