The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides

J Biotechnol. 2015 Jun 20;204:7-12. doi: 10.1016/j.jbiotec.2015.02.036. Epub 2015 Mar 24.

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.

Keywords: (R)-3-hydroxyalkanoic acids; 3-Chlorodecanoic acid; Anti-cancer; Bioactive peptides; Carbon chain length.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Carbon / analysis
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Circular Dichroism
  • Decanoic Acids / chemistry*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Molecular Structure
  • Peptides / chemistry*
  • Polyhydroxyalkanoates / chemistry*
  • Regression Analysis
  • Tetrazolium Salts
  • Thiazoles

Substances

  • Antineoplastic Agents
  • Decanoic Acids
  • Peptides
  • Polyhydroxyalkanoates
  • Tetrazolium Salts
  • Thiazoles
  • Carbon
  • thiazolyl blue
  • myrmicacin