Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules.
Short peptide sequences that are able to transport molecules across the cell membrane have been developed as tools for intracellular delivery of therapeutic molecules. This work describes a novel family of cell-penetrating peptides named Vectocell peptides [also termed DPVs (Diatos peptide vectors)]. These peptides, originating from human heparin binding proteins and/or anti-DNA antibodies, once conjugated to a therapeutic molecule, can deliver the molecule to either the cytoplasm or the nucleus of mammalian cells. Vectocell peptides can drive intracellular delivery of molecules of varying molecular mass, including full-length active immunoglobulins, with efficiency often greater than that of the well-characterized cell-penetrating peptide Tat. The internalization of Vectocell peptides has been demonstrated to occur in both adherent and suspension cell lines as well as in primary cells through an energy-dependent endocytosis process, involving cell-membrane lipid rafts. This endocytosis occurs after binding of the cell-penetrating peptides to extracellular heparan sulphate proteoglycans, except for one particular peptide (DPV1047) that partially originates from an anti-DNA antibody and is internalized in a caveolar independent manner. These new therapeutic tools are currently being developed for intracellular delivery of a number of active molecules and their potentiality for in vivo transduction investigated.
De Coupade
Catherine
C
Diatos S.A., 166 Boulevard du Montparnasse, 75014 Paris, France. cdecoupade@diatos.com
Fittipaldi
Antonio
A
Chagnas
Vanessa
V
Michel
Matthieu
M
Carlier
Sophie
S
Tasciotti
Ennio
E
Darmon
Audrey
A
Ravel
Denis
D
Kearsey
Jonathan
J
Giacca
Mauro
M
Cailler
Françoise
F
D000595:Amino Acid Sequence; D000818:Animals; D001287:Attachment Sites, Microbiological / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D013696:Temperature; D014764:Viral Proteins / Q000378:metabolism
D004337:Drug Carriers; D010455:Peptides; D011994:Recombinant Proteins; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases