TY  - JOUR
AU  - Almahboub, Sarah A.
AU  - Narancić, Tanja
AU  - Devocelle, Marc
AU  - Kenny, Shane T.
AU  - Palmer-Brown, William
AU  - Murphy, Cormac
AU  - Nikodinović-Runić, Jasmina
AU  - O'Connor, Kevin 
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1161
AB  - Terminal modification of peptides is frequently used to improve their hydrophobicity. While N-terminal modification with fatty acids (lipidation) has been reported previously, C-terminal lipidation is limited as it requires the use of linkers. Here we report the use of a biocatalyst for the production of an unnatural fatty amino acid, (S)-2-aminooctanoic acid (2-AOA) with enantiomeric excess  gt  98% ee and the subsequent use of 2-AOA to modify and improve the activity of an antimicrobial peptide. A transaminase originating from Chromobacterium violaceum was employed with a conversion efficiency 52-80% depending on the ratio of amino group donor to acceptor. 2-AOA is a fatty acid with amino functionality, which allowed direct C- and N-terminal conjugation respectively to an antimicrobial peptide (AMP) derived from lactoferricin B. The antibacterial activity of the modified peptides was improved by up to 16-fold. Furthermore, minimal inhibitory concentrations (MIC) of C-terminally modified peptide were always lower than N-terminally conjugated peptides. The C-terminally modified peptide exhibited MIC values of 25 mu g/ml for Escherichia coli, 50 mu g/ml for Bacillus subtilis, 100 mu g/ml for Salmonella typhimurium, 200 mu g/ml for Pseudomonas aeruginosa and 400 mu g/ml for Staphylococcus aureus. The C-terminally modified peptide was the only peptide tested that showed complete inhibition of growth of S. aureus.
PB  - Springer, New York
T2  - Applied Microbiology and Biotechnology
T1  - Biosynthesis of 2-aminooctanoic acid and its use to terminally modify a lactoferricin B peptide derivative for improved antimicrobial activity
EP  - 799
IS  - 2
SP  - 789
VL  - 102
DO  - 10.1007/s00253-017-8655-0
ER  - 

@article{
author = "Almahboub, Sarah A. and Narancić, Tanja and Devocelle, Marc and Kenny, Shane T. and Palmer-Brown, William and Murphy, Cormac and Nikodinović-Runić, Jasmina and O'Connor, Kevin ",
year = "2018",
abstract = "Terminal modification of peptides is frequently used to improve their hydrophobicity. While N-terminal modification with fatty acids (lipidation) has been reported previously, C-terminal lipidation is limited as it requires the use of linkers. Here we report the use of a biocatalyst for the production of an unnatural fatty amino acid, (S)-2-aminooctanoic acid (2-AOA) with enantiomeric excess  gt  98% ee and the subsequent use of 2-AOA to modify and improve the activity of an antimicrobial peptide. A transaminase originating from Chromobacterium violaceum was employed with a conversion efficiency 52-80% depending on the ratio of amino group donor to acceptor. 2-AOA is a fatty acid with amino functionality, which allowed direct C- and N-terminal conjugation respectively to an antimicrobial peptide (AMP) derived from lactoferricin B. The antibacterial activity of the modified peptides was improved by up to 16-fold. Furthermore, minimal inhibitory concentrations (MIC) of C-terminally modified peptide were always lower than N-terminally conjugated peptides. The C-terminally modified peptide exhibited MIC values of 25 mu g/ml for Escherichia coli, 50 mu g/ml for Bacillus subtilis, 100 mu g/ml for Salmonella typhimurium, 200 mu g/ml for Pseudomonas aeruginosa and 400 mu g/ml for Staphylococcus aureus. The C-terminally modified peptide was the only peptide tested that showed complete inhibition of growth of S. aureus.",
publisher = "Springer, New York",
journal = "Applied Microbiology and Biotechnology",
title = "Biosynthesis of 2-aminooctanoic acid and its use to terminally modify a lactoferricin B peptide derivative for improved antimicrobial activity",
pages = "799-789",
number = "2",
volume = "102",
doi = "10.1007/s00253-017-8655-0"
}

Almahboub, S. A., Narancić, T., Devocelle, M., Kenny, S. T., Palmer-Brown, W., Murphy, C., Nikodinović-Runić, J.,& O'Connor, K.. (2018). Biosynthesis of 2-aminooctanoic acid and its use to terminally modify a lactoferricin B peptide derivative for improved antimicrobial activity. in Applied Microbiology and Biotechnology
Springer, New York., 102(2), 789-799.
https://doi.org/10.1007/s00253-017-8655-0

Almahboub SA, Narancić T, Devocelle M, Kenny ST, Palmer-Brown W, Murphy C, Nikodinović-Runić J, O'Connor K. Biosynthesis of 2-aminooctanoic acid and its use to terminally modify a lactoferricin B peptide derivative for improved antimicrobial activity. in Applied Microbiology and Biotechnology. 2018;102(2):789-799.
doi:10.1007/s00253-017-8655-0 .

Almahboub, Sarah A., Narancić, Tanja, Devocelle, Marc, Kenny, Shane T., Palmer-Brown, William, Murphy, Cormac, Nikodinović-Runić, Jasmina, O'Connor, Kevin , "Biosynthesis of 2-aminooctanoic acid and its use to terminally modify a lactoferricin B peptide derivative for improved antimicrobial activity" in Applied Microbiology and Biotechnology, 102, no. 2 (2018):789-799,
https://doi.org/10.1007/s00253-017-8655-0 . .

TY  - JOUR
AU  - Szwej, Emilia
AU  - Devocelle, Marc
AU  - Kenny, Shane
AU  - Guzik, Maciej
AU  - O'Connor, Stephen
AU  - Nikodinović-Runić, Jasmina
AU  - Milovanović, Jelena
AU  - Maslak, Veselin
AU  - Byrne, Annete T.
AU  - Gallagher, William M.
AU  - Zulian, Qun Ren
AU  - Zinn, Manfred
AU  - O'Connor, Kevin 
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/877
AB  - 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 (R3HA5) can enhance peptide activity, if chain length affects enhancement, and what effect R3HA5 have on peptide structure. Here we show that the degree of enhancement of peptide (DP18L) anti-cancer activity by R3HA5 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, R3HA5 with 9 and 10 carbons were most effective at improving DPI 8L activity. DPI 8L peptide variant DPI 7L, 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 DPI 7L returned the helix content back to levels of DPI 8L. However (R)-3-hydroxyhexanoic did not enhance the anti-cancer activity of DPI 7L 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 R3HA5, (R)-3-hydroxydecanoic acid was synthetically converted to (+/-)3-chlorodecanoic acid, which when conjugated to DP18L improved its antiproliferative activity against MiaPaCa cells.
PB  - Elsevier Science Bv, Amsterdam
T2  - Journal of Biotechnology
T1  - The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides
EP  - 12
SP  - 7
VL  - 204
DO  - 10.1016/j.jbiotec.2015.02.036
ER  - 

@article{
author = "Szwej, Emilia and Devocelle, Marc and Kenny, Shane and Guzik, Maciej and O'Connor, Stephen and Nikodinović-Runić, Jasmina and Milovanović, Jelena and Maslak, Veselin and Byrne, Annete T. and Gallagher, William M. and Zulian, Qun Ren and Zinn, Manfred and O'Connor, Kevin ",
year = "2015",
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 (R3HA5) can enhance peptide activity, if chain length affects enhancement, and what effect R3HA5 have on peptide structure. Here we show that the degree of enhancement of peptide (DP18L) anti-cancer activity by R3HA5 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, R3HA5 with 9 and 10 carbons were most effective at improving DPI 8L activity. DPI 8L peptide variant DPI 7L, 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 DPI 7L returned the helix content back to levels of DPI 8L. However (R)-3-hydroxyhexanoic did not enhance the anti-cancer activity of DPI 7L 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 R3HA5, (R)-3-hydroxydecanoic acid was synthetically converted to (+/-)3-chlorodecanoic acid, which when conjugated to DP18L improved its antiproliferative activity against MiaPaCa cells.",
publisher = "Elsevier Science Bv, Amsterdam",
journal = "Journal of Biotechnology",
title = "The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides",
pages = "12-7",
volume = "204",
doi = "10.1016/j.jbiotec.2015.02.036"
}

Szwej, E., Devocelle, M., Kenny, S., Guzik, M., O'Connor, S., Nikodinović-Runić, J., Milovanović, J., Maslak, V., Byrne, A. T., Gallagher, W. M., Zulian, Q. R., Zinn, M.,& O'Connor, K.. (2015). The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides. in Journal of Biotechnology
Elsevier Science Bv, Amsterdam., 204, 7-12.
https://doi.org/10.1016/j.jbiotec.2015.02.036

Szwej E, Devocelle M, Kenny S, Guzik M, O'Connor S, Nikodinović-Runić J, Milovanović J, Maslak V, Byrne AT, Gallagher WM, Zulian QR, Zinn M, O'Connor K. The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides. in Journal of Biotechnology. 2015;204:7-12.
doi:10.1016/j.jbiotec.2015.02.036 .

Szwej, Emilia, Devocelle, Marc, Kenny, Shane, Guzik, Maciej, O'Connor, Stephen, Nikodinović-Runić, Jasmina, Milovanović, Jelena, Maslak, Veselin, Byrne, Annete T., Gallagher, William M., Zulian, Qun Ren, Zinn, Manfred, O'Connor, Kevin , "The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides" in Journal of Biotechnology, 204 (2015):7-12,
https://doi.org/10.1016/j.jbiotec.2015.02.036 . .

TY  - JOUR
AU  - O'Connor, Stephen
AU  - Szwej, Emilia
AU  - Nikodinović-Runić, Jasmina
AU  - O'Connor, Aisling
AU  - Byrne, Annette T.
AU  - Devocelle, Marc
AU  - O'Donovan, Norma
AU  - Gallagher, William M.
AU  - Babu, Ramesh
AU  - Kenny, Shane T.
AU  - Zinn, Manfred
AU  - Zulian, Qun Ren
AU  - O'Connor, Kevin 
PY  - 2013
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/637
AB  - The biodegradable polymer medium chain length polyhydroxyalkanoate (mclPHA), produced by Pseudomonas putida CA-3, was depolymerised and the predominant monomer (R)-3-hydroxydecanoic acid (R10) purified. R10 was conjugated to a D-peptide DP18 and its derivatives. All peptides conjugated with R10 exhibited greater anti-cancer activity compared to the unconjugated peptides. Unconjugated and conjugated peptides were cytocidal for cancer cells. Conjugation of R10 to peptides was essential for enhanced anti-proliferation activity, as unconjugated mixes did not result in enhancement of anti-cancer activity. The conjugation of R10 resulted in more rapid uptake of peptides into HeLa and MiaPaCa cells compared to unconjugated peptide. Both unconjugated and R10 conjugated peptides localized to the mitochondria of HeLa and MiaPaCa cells and induced apoptosis. Peptide conjugated with a terminally hydroxylated decanoic acid (omega-hydroxydecanoic acid) exhibited 3.3 and 6.3 fold higher IC50 values compared to R10 conjugated peptide indicating a role for the position of the hydroxyl moiety in enhancement of anti-cancer activity. Conjugation of decanoic acid (C10) to peptides resulted in similar or higher IC50 values compared to R10 conjugates but C10 conjugates did not exhibit any cancer selectivity. Combination studies showed that R10DP18L exhibited synergy with cisplatin, gemcitabine, and taxotere with IC50 values in the nanomolar range.
PB  - Elsevier Sci Ltd, Oxford
T2  - Biomaterials
T1  - The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate
EP  - 2718
IS  - 11
SP  - 2710
VL  - 34
DO  - 10.1016/j.biomaterials.2012.12.032
ER  - 

@article{
author = "O'Connor, Stephen and Szwej, Emilia and Nikodinović-Runić, Jasmina and O'Connor, Aisling and Byrne, Annette T. and Devocelle, Marc and O'Donovan, Norma and Gallagher, William M. and Babu, Ramesh and Kenny, Shane T. and Zinn, Manfred and Zulian, Qun Ren and O'Connor, Kevin ",
year = "2013",
abstract = "The biodegradable polymer medium chain length polyhydroxyalkanoate (mclPHA), produced by Pseudomonas putida CA-3, was depolymerised and the predominant monomer (R)-3-hydroxydecanoic acid (R10) purified. R10 was conjugated to a D-peptide DP18 and its derivatives. All peptides conjugated with R10 exhibited greater anti-cancer activity compared to the unconjugated peptides. Unconjugated and conjugated peptides were cytocidal for cancer cells. Conjugation of R10 to peptides was essential for enhanced anti-proliferation activity, as unconjugated mixes did not result in enhancement of anti-cancer activity. The conjugation of R10 resulted in more rapid uptake of peptides into HeLa and MiaPaCa cells compared to unconjugated peptide. Both unconjugated and R10 conjugated peptides localized to the mitochondria of HeLa and MiaPaCa cells and induced apoptosis. Peptide conjugated with a terminally hydroxylated decanoic acid (omega-hydroxydecanoic acid) exhibited 3.3 and 6.3 fold higher IC50 values compared to R10 conjugated peptide indicating a role for the position of the hydroxyl moiety in enhancement of anti-cancer activity. Conjugation of decanoic acid (C10) to peptides resulted in similar or higher IC50 values compared to R10 conjugates but C10 conjugates did not exhibit any cancer selectivity. Combination studies showed that R10DP18L exhibited synergy with cisplatin, gemcitabine, and taxotere with IC50 values in the nanomolar range.",
publisher = "Elsevier Sci Ltd, Oxford",
journal = "Biomaterials",
title = "The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate",
pages = "2718-2710",
number = "11",
volume = "34",
doi = "10.1016/j.biomaterials.2012.12.032"
}

O'Connor, S., Szwej, E., Nikodinović-Runić, J., O'Connor, A., Byrne, A. T., Devocelle, M., O'Donovan, N., Gallagher, W. M., Babu, R., Kenny, S. T., Zinn, M., Zulian, Q. R.,& O'Connor, K.. (2013). The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate. in Biomaterials
Elsevier Sci Ltd, Oxford., 34(11), 2710-2718.
https://doi.org/10.1016/j.biomaterials.2012.12.032

O'Connor S, Szwej E, Nikodinović-Runić J, O'Connor A, Byrne AT, Devocelle M, O'Donovan N, Gallagher WM, Babu R, Kenny ST, Zinn M, Zulian QR, O'Connor K. The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate. in Biomaterials. 2013;34(11):2710-2718.
doi:10.1016/j.biomaterials.2012.12.032 .

O'Connor, Stephen, Szwej, Emilia, Nikodinović-Runić, Jasmina, O'Connor, Aisling, Byrne, Annette T., Devocelle, Marc, O'Donovan, Norma, Gallagher, William M., Babu, Ramesh, Kenny, Shane T., Zinn, Manfred, Zulian, Qun Ren, O'Connor, Kevin , "The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate" in Biomaterials, 34, no. 11 (2013):2710-2718,
https://doi.org/10.1016/j.biomaterials.2012.12.032 . .