title: Engineered Nanostructured Facial Lipopeptide as Highly Efficient Molecular Transporter.
abstract: Designing an effective peptide based molecular transporter for the intracellular delivery of hydrophilic therapeutic biomacromolecules remains a considerable challenge. Highly basic oligoarginine and lipidated arginine rich cell penetrating peptides have been reported in the literature as molecular transporters, which were extensively used for cellular internalization of significantly large biopharmaceuticals. However, oligoarginine based molecular transporters with l-arginine residues pose significant challenges due to proteolytic instability and limited stability of noncovalent peptide-cargo nanocomplexes. Exploiting the rational peptide designing strategy, we have engineered protease-resistant facial lipopeptide based molecular transporter having arginine-sarcosine-arginine moiety to minimize adjacent arginine-arginine pair repulsion. N-Methylated amino acid sarcosine was incorporated as a spacer between two adjacent arginine residues, which provides proteolytic stability to the designed peptide and minimizes intermolecular aggregation of peptides. Two stearyl moieties were incorporated to facilitate cellular internalization. Interestingly, our designed lipopeptide exhibits significantly enhanced cellular internalization with only six l-arginine residues compared to stearylated oligo-nona-arginine. Additionally, enhanced proteolytic stability of such class of molecular transporter enables increased cargo internalization, and we anticipate that our engineered multifunctional, proteolytically stable, nanostructured facial lipopeptide based molecular transporter can have major impact in advancing drug delivery technologies.
authors.affiliation: Department of Chemical Sciences and ‡Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata , Mohanpur 741246, West Bengal, India.
authors.forename: Chiranjit
authors.initials: C
authors.lastname: Dutta
authors.affiliation: Department of Chemical Sciences and ‡Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata , Mohanpur 741246, West Bengal, India.
authors.forename: Kasturee
authors.initials: K
authors.lastname: Chakraborty
authors.affiliation: Department of Chemical Sciences and ‡Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata , Mohanpur 741246, West Bengal, India.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Sinha Roy
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D004337:Drug Carriers / Q000737:chemistry; D000067493:Dynamic Light Scattering; D019793:Fluorescein / Q000737:chemistry; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D018613:Microscopy, Confocal; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000378:metabolism; D012521:Sarcosine / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D004337:Drug Carriers; D055666:Lipopeptides; D034741:RNA, Small Interfering; D001120:Arginine; D019793:Fluorescein; D012521:Sarcosine
keywords: biopharmaceuticals; drug delivery; lipopeptide; molecular transporter; nanoparticle; peptides