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Optimization of adiponectin‐derived peptides for inhibition of cancer cell growth and signaling
Author(s) -
Otvos Laszlo,
Kovalszky Ilona,
Olah Julia,
Coroniti Roberta,
Knappe Daniel,
Nollmann Friederike I.,
Hoffmann Ralf,
Wade John D.,
Lovas Sandor,
Surmacz Eva
Publication year - 2015
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22627
Subject(s) - chemistry , agonist , adiponectin , receptor , signal transduction , peptide , antagonist , leptin , pharmacology , endocrinology , medicine , microbiology and biotechnology , biochemistry , biology , insulin resistance , insulin , obesity
Adiponectin, an adipose tissue‐excreted adipokine plays protective roles in metabolic and cardiovascular diseases and exerts anti‐cancer activities, partially by interfering with leptin‐induced signaling. Previously we identified the active site in the adiponectin protein, and generated both a nanomolar monomeric agonist of the adiponectin receptor (10‐mer ADP355) and an antagonist (8‐mer ADP400) to modulate various adiponectin receptor‐mediated cellular functions. As physiologically circulating adiponectin forms multimeric complexes, we also generated an agonist dimer with improved biodistribution and in vitro efficacy. In the current report, we attempted to optimize the monomeric agonist structure. Neither extension of the peptide up to 14‐mer analogs nor reinstallation of native residues in permissible positions enhanced significantly the activity profile. The only substitutions that resulted in 5–10‐fold improved agonistic activity were the replacement of turn‐forming Gly4 and Tyr7 residues with Pro and Hyp, respectively, yielding the more active native β‐sheet structure. All peptides retained good stability in human serum exhibiting half‐lives >2 h. The cellular efficacy and stability rankings among the peptides followed expected structure–activity relationship trends. To investigate whether simultaneous activation of adiponectin pathways and inhibition of leptin‐induced signals can result in cytostatic and anti‐oncogenic signal transduction processes, we developed a chimera of the leptin receptor antagonist peptide Allo‐aca (placed to the N‐terminus) and ADP355 (at the C‐terminus). The in vitro anti‐tumor activity and intracellular signaling of the chimera were dominated by the more active Allo‐aca component. The ADP355 part, however, reversed unfavorable in vivo metabolic effects of the leptin receptor antagonist. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 156–166, 2015.