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

Szwej, Emilia (University College Dublin, Dublin, Ireland) ; Devocelle, Marc (Royal college of Surgeons in Ireland, Dublin, Ireland) ; Kenny, Shane (University College Dublin, Dublin, Ireland) ; Guzik, Maciej (University College Dublin, Dublin, Ireland) ; O'Connor, Stephen (University College Dublin, Dublin, Ireland) ; Nikodinovic-Runic, Jasmina (University of Belgrade, Belgrade, Serbia) ; Radivojevic, Jelena (University of Belgrade, Belgrade, Serbia) ; Maslak, Veselin (University of Belgrade, Belgrade, Serbia) ; Byrne, Annete T. (University College Dublin, Dublin, Ireland ; Royal college of Surgeon in Ireland, Dublin, Ireland) ; Gallagher, William M. (University College Dublin, Dublin, Ireland) ; Zulian, Qun Ren (Empa Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Biomaterials, St. Gallen, Switzerland) ; Zinn, Manfred (Empa Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Biomaterials, St. Gallen, Switzerland) ; O'Connor, Kevin E. (University College Dublin, Dublin, Ireland)

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.

Note: ZINN, Manfred est un chercheur à la HES-SO, HEI-VS, depuis 2011.

Article Type:
Ingénierie et Architecture
Institut Technologies du vivant
6 p.
Published in:
Journal of Biotechnology
Numeration (vol. no.):
2015, vol. 204, no. 10, pp. 7-12
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 Record created 2021-06-25, last modified 2021-07-05

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