Functional cell permeable motifs within medically relevant proteins.
Increasing experimental evidence indicates that short polybasic peptides are able to translocate across the membrane of living cells. However, these peptides, often derived from viruses and insects, may induce unspecific effects that could mask the action of their cargoes. Here, we show that a panel of lysine and/or arginine-rich peptides, derived from human proteins involved in cell signalling pathways leading to inflammation, possess the intrinsic ability to cross intact cellular membranes. These peptides are also capable of carrying a biologically active cargo. One of these peptides, encompassing the cell permeable sequence of the Toll-receptor 4 (TLR4) adaptor protein (TIRAP) and modified to carry a dominant-negative domain of the same TIRAP protein, selectively inhibited the production of pro-inflammatory cytokines upon LPS challenge, in in vitro, ex vivo and in vivo experiments. Docking studies indicated that this inhibition might be mediated by the disruption of the recruitment of downstream effector molecules. These results show for the first time the potential of using for therapy cell permeable peptides derived from human proteins involved in disease.
Low
Walter
W
Biological Sciences, Imperial College London, Imperial College Road, 5th floor SAF Building, London SW7 2AZ, UK. w.low@imperial.ac.uk
Mortlock
Alison
A
Petrovska
Liljana
L
Dottorini
Tania
T
Dougan
Gordon
G
Crisanti
Andrea
A
D020816:Amino Acid Motifs / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D010539:Permeability; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D008562:Membrane Glycoproteins; D010455:Peptides; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse