title: The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides.
abstract: Conjugation of DP18L peptide with (R)-3-hydroxydecanoic acid, derived from the biopolymer polyhydroxyalkanoate, enhances its anti-cancer activity (O'Connor et al., 2013. Biomaterials 34, 2710-2718). However, it is unknown if other (R)-3-hydroxyalkanoic acids (R3HAs) can enhance peptide activity, if chain length affects enhancement, and what effect R3HAs have on peptide structure. Here we show that the degree of enhancement of peptide (DP18L) anti-cancer activity by R3HAs is carbon chain length dependent. In all but one example the R3HA conjugated peptides were more active against cancer cells than the unconjugated peptides. However, R3HAs with 9 and 10 carbons were most effective at improving DP18L activity. DP18L peptide variant DP17L, missing a hydrophobic amino acid (leucine residue 4) exhibited lower efficacy against MiaPaCa cells. Circular dichroism analysis showed DP17L had a lower alpha helix content and the conjugation of any R3HA ((R)-3-hydroxyhexanoic acid to (R)-3-hydroxydodecanoic acid) to DP17L returned the helix content back to levels of DP18L. However (R)-3-hydroxyhexanoic did not enhance the anti-cancer activity of DP17L and at least 7 carbons were needed in the R3HA to enhance activity of D17L. DP17L needs a longer chain R3HA to achieve the same activity as DP18L conjugated to an R3HA. As a first step to assess the synthetic potential of polyhydroxyalkanoate derived R3HAs, (R)-3-hydroxydecanoic acid was synthetically converted to (±)3-chlorodecanoic acid, which when conjugated to DP18L improved its antiproliferative activity against MiaPaCa cells.
authors.affiliation: School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Szwej
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical & Medicinal Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Marc
authors.initials: M
authors.lastname: Devocelle
authors.affiliation: School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Shane
authors.initials: S
authors.lastname: Kenny
authors.affiliation: School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Guzik
authors.affiliation: School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Connor
authors.affiliation: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Nikodinovic-Runic
authors.affiliation: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia; Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Radivojevic
authors.affiliation: Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Veselin
authors.initials: V
authors.lastname: Maslak
authors.affiliation: School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Dublin, Ireland; Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Annete T
authors.initials: AT
authors.lastname: Byrne
authors.affiliation: School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.affiliation: Empa Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Biomaterials, St. Gallen, Switzerland.
authors.forename: Qun Ren
authors.initials: QR
authors.lastname: Zulian
authors.affiliation: Empa Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Biomaterials, St. Gallen, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Zinn
authors.affiliation: School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Dublin, Ireland. Electronic address: kevin.oconnor@ucd.ie.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: O'Connor
mesh_terms: D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002244:Carbon / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D003652:Decanoic Acids / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D054813:Polyhydroxyalkanoates / Q000737:chemistry*; D012044:Regression Analysis; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000970:Antineoplastic Agents; D003652:Decanoic Acids; D010455:Peptides; D054813:Polyhydroxyalkanoates; D013778:Tetrazolium Salts; D013844:Thiazoles; D002244:Carbon; C022616:thiazolyl blue; C017552:myrmicacin
keywords: (R)-3-hydroxyalkanoic acids; 3-Chlorodecanoic acid; Anti-cancer; Bioactive peptides; Carbon chain length