A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice.
Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with DeltaPsi(m) loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.
Brabant
Magali
M
Theraptosis Research Laboratory, Pasteur BioTop, 75015, Paris, France.
Baux
Ludwig
L
Casimir
Richard
R
Briand
Jean Paul
JP
Chaloin
Olivier
O
Porceddu
Mathieu
M
Buron
Nelly
N
Chauvier
David
D
Lassalle
Myriam
M
Lecoeur
Hervé
H
Langonné
Alain
A
Dupont
Sylvie
S
Déas
Olivier
O
Brenner
Catherine
C
Rebouillat
Dominique
D
Muller
Sylviane
S
Borgne-Sanchez
Annie
A
Jacotot
Etienne
E
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005416:Flavivirus / Q000737:chemistry*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D016019:Survival Analysis; D014764:Viral Proteins / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology
D010455:Peptides; D014764:Viral Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus