Inhibiting the inhibitors: retro-inverso Smac peptides.
Resistance against apoptosis-inducing anti-cancer drugs remains a severe problem in therapy. One reason is the overexpression of inhibitors of apoptosis proteins (IAPs), a group of proteins responsible for the prevention of apoptosis induction by inactivation of initiator caspases. The natural inhibitor of the IAPs is the protein Smac, which impedes the binding to the caspases. Although Smac is a potent inhibitor, Smac peptides are not very stable in vivo and thus not applicable in therapy. Bioinformatical methods were applied to design Smac-derived peptides to break the therapy resistance in IAP high-expressing tumor cells. The exchange of amino acids in the Smac peptides AVPI and AVPF against unnatural amino acids leads to an improvement of the apoptosis sensitivity. The variety of Smac peptides was filtered by computational docking. Moreover, Smac-derived peptides with sufficient binding to the IAPs were tested in IAP-expressing Hodgkin Lymphoma cell lines.
Hossbach
Julia
J
Charité - Universitätsmedizin Berlin, Institute of Physiology, Structural Bioinformatics Group, Arnimallee 22, 14195 Berlin, Germany. Julia.Hossbach@charite.de
Michalsky
Elke
E
Henklein
Peter
P
Jaeger
Marten
M
Daniel
Peter T
PT
Preissner
Robert
R
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019295:Computational Biology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding
D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; C532637:SMAC peptide