Design and synthesis of biologically active peptides: a 'tail' of amino acids can modulate activity of synthetic cyclic peptides.
In earlier work, we synthesized a cyclic 9-amino acid peptide (AFPep, cyclo[EKTOVNOGN]) and showed it to be useful for prevention and therapy of breast cancer. In an effort to explore the structure-function relationships of AFPep, we have designed analogs that bear a short 'tail' (one or two amino acids) attached to the cyclic peptide distal to its pharmacophore. Analogs that bore a tail of either one or two amino acids, either of which had a hydrophilic moiety in the side chain (e.g., cyclo[EKTOVNOGN]FS) exhibited greatly diminished biological activity (inhibition of estrogen-stimulated uterine growth) relative to AFPep. Analogs that bore a tail of either one or two amino acids which had hydrophobic (aliphatic or aromatic) side chains (e.g., cyclo[EKTOVNOGN]FI) retained (or had enhanced) growth inhibition activity. Combining in the same biological assay a hydrophilic-tailed analog with either AFPep or a hydrophobic-tailed analog resulted in decreased activity relative to that for AFPep or for the hydrophobic-tailed analog alone, suggesting that hydrophilic-tailed analogs are binding to a biologically active receptor. An analog with a disrupted pharmacophore (cyclo[EKTOVGOGN]) exhibited little or no growth inhibition activity. An analog with a hydrophilic tail and a disrupted pharmacophore (cyclo[EKTOVGOGN]FS) exhibited no growth inhibition activity of its own and did not affect the activity of a hydrophobic-tailed analog, but enhanced the growth inhibition activity of AFPep. These results are discussed in the context of a two-receptor model for binding of AFPep and ring-and-tail analogs. We suggest that tails on cyclic peptides may comprise a useful method to enhance diversity of peptide design and specificity of ligand-receptor interactions.
Center for Cardiovascular Science, Albany Medical College, Albany, NY 12208, USA.
Alberto
A
Bryan
Leroy
L
Joseph
James A
JA
Bennett
Herbert I
HI
Jacobson
Thomas T
TT
Andersen
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014599:Uterus / Q000187:drug effects / Q000254:growth & development; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000737:chemistry
D000596:Amino Acids; D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D011956:Receptors, Cell Surface; D000509:alpha-Fetoproteins; D004958:Estradiol