title: Structural rearrangements and chemical modifications in known cell penetrating peptide strongly enhance DNA delivery efficiency.
abstract: Amphipathic peptides with unusual cellular translocation properties have been used as carriers of different biomolecules. However, the parameters which control the delivery efficiency of a particular cargo by a peptide and the selectivity of cargo delivery are not very well understood. In this work, we have used the known cell penetrating peptide pVEC (derived from VE-cadherin) and systematically changed its amphipathicity (from primary to secondary) as well as the total charge and studied whether these changes influence the plasmid DNA condensation ability, cellular uptake of the peptide-DNA complexes and in turn the efficiency of DNA delivery of the peptide. Our results show that although the efficiency of DNA delivery of pVEC is poor, modification of the same peptide to create a combination of nine arginines along with secondary amphipathicity improves its plasmid DNA delivery efficiency, particularly in presence of an endosomotropic agent like chloroquine. In addition, presence of histidines along with 9 arginines and secondary amphipathicity shows efficient DNA delivery with low toxicity even in absence of chloroquine in multiple cell lines. We attribute these enhancements in transfection efficiency to the differences in the mechanism of complex formation by the different variants of the parent peptide which in turn are related to the chemical nature of the peptide itself. These results exhibit the importance of understanding the physicochemical parameters of the carrier and complex in modulating gene delivery efficiency. Such studies can be helpful in improving peptide design for delivery of different cargo molecules.
authors: Institute of Genomics and Integrative Biology (CSIR), Mall Road, Delhi 110007, India.
authors: Rajpal
authors: Anita
authors: A
authors: Mann
authors: Richa
authors: R
authors: Khanduri
authors: Rangeetha J
authors: RJ
authors: Naik
authors: Munia
authors: M
authors: Ganguli
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage*; D016466:CHO Cells; D015820:Cadherins / Q000008:administration & dosage*; D002470:Cell Survival; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage*; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000008:administration & dosage*; D018014:Gene Transfer Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D057846:Cell-Penetrating Peptides; D004247:DNA; D007770:L-Lactate Dehydrogenase; D000099152:Cadherin 5