Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma
The study investigates the antitumor effect of two cationic peptides, R-DIM-P-LF11-215 (RDP215) and the D-amino acid variant 9D-R-DIM-P-LF11-215 (9D-RDP215), targeting the negatively charged lipid phosphatidylserine (PS) exposed by cancer cells, such as of melanoma and glioblastoma. Model studies mi...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/16/8469 |
| _version_ | 1797523634849316864 |
|---|---|
| author | Theresa Maxian Lisa Gerlitz Sabrina Riedl Beate Rinner Dagmar Zweytick |
| author_facet | Theresa Maxian Lisa Gerlitz Sabrina Riedl Beate Rinner Dagmar Zweytick |
| author_sort | Theresa Maxian |
| collection | DOAJ |
| description | The study investigates the antitumor effect of two cationic peptides, R-DIM-P-LF11-215 (RDP215) and the D-amino acid variant 9D-R-DIM-P-LF11-215 (9D-RDP215), targeting the negatively charged lipid phosphatidylserine (PS) exposed by cancer cells, such as of melanoma and glioblastoma. Model studies mimicking cancer and non-cancer membranes revealed the specificity for the cancer-mimic PS by both peptides with a slightly stronger impact by the D-peptide. Accordingly, membrane effects studied by DSC, leakage and quenching experiments were solely induced by the peptides when the cancer mimic PS was present. Circular dichroism revealed a sole increase in β-sheet conformation in the presence of the cancer mimic for both peptides; only 9D-RDP215 showed increased structure already in the buffer. Ex vitro stability studies by SDS-PAGE as well as in vitro with melanoma A375 revealed a stabilizing effect of D-amino acids in the presence of serum, which was also confirmed in 2D and 3D in vitro experiments on glioblastoma LN-229. 9D-RDP215 was additionally able to pass a BBB model, whereupon it induced significant levels of cell death in LN-229 spheroids. Summarized, the study encourages the introduction of D-amino acids in the design of antitumor peptides for the improvement of their stable antitumor activity. |
| first_indexed | 2024-03-10T08:45:50Z |
| format | Article |
| id | doaj.art-5fb026317dd940b6a9f1c60bcab1bb71 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:45:50Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5fb026317dd940b6a9f1c60bcab1bb712023-11-22T07:55:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216846910.3390/ijms22168469Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and GlioblastomaTheresa Maxian0Lisa Gerlitz1Sabrina Riedl2Beate Rinner3Dagmar Zweytick4Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50/III, A-8010 Graz, AustriaInstitute of Molecular Biosciences, University of Graz, Humboldtstraße 50/III, A-8010 Graz, AustriaInstitute of Molecular Biosciences, University of Graz, Humboldtstraße 50/III, A-8010 Graz, AustriaBioTechMed-Graz, A-8010 Graz, AustriaInstitute of Molecular Biosciences, University of Graz, Humboldtstraße 50/III, A-8010 Graz, AustriaThe study investigates the antitumor effect of two cationic peptides, R-DIM-P-LF11-215 (RDP215) and the D-amino acid variant 9D-R-DIM-P-LF11-215 (9D-RDP215), targeting the negatively charged lipid phosphatidylserine (PS) exposed by cancer cells, such as of melanoma and glioblastoma. Model studies mimicking cancer and non-cancer membranes revealed the specificity for the cancer-mimic PS by both peptides with a slightly stronger impact by the D-peptide. Accordingly, membrane effects studied by DSC, leakage and quenching experiments were solely induced by the peptides when the cancer mimic PS was present. Circular dichroism revealed a sole increase in β-sheet conformation in the presence of the cancer mimic for both peptides; only 9D-RDP215 showed increased structure already in the buffer. Ex vitro stability studies by SDS-PAGE as well as in vitro with melanoma A375 revealed a stabilizing effect of D-amino acids in the presence of serum, which was also confirmed in 2D and 3D in vitro experiments on glioblastoma LN-229. 9D-RDP215 was additionally able to pass a BBB model, whereupon it induced significant levels of cell death in LN-229 spheroids. Summarized, the study encourages the introduction of D-amino acids in the design of antitumor peptides for the improvement of their stable antitumor activity.https://www.mdpi.com/1422-0067/22/16/8469antitumor peptidesD-amino acidsserum stabilitymelanomaglioblastoma |
| spellingShingle | Theresa Maxian Lisa Gerlitz Sabrina Riedl Beate Rinner Dagmar Zweytick Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma International Journal of Molecular Sciences antitumor peptides D-amino acids serum stability melanoma glioblastoma |
| title | Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma |
| title_full | Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma |
| title_fullStr | Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma |
| title_full_unstemmed | Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma |
| title_short | Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma |
| title_sort | effect of l to d amino acid substitution on stability and activity of antitumor peptide rdp215 against human melanoma and glioblastoma |
| topic | antitumor peptides D-amino acids serum stability melanoma glioblastoma |
| url | https://www.mdpi.com/1422-0067/22/16/8469 |
| work_keys_str_mv | AT theresamaxian effectofltodaminoacidsubstitutiononstabilityandactivityofantitumorpeptiderdp215againsthumanmelanomaandglioblastoma AT lisagerlitz effectofltodaminoacidsubstitutiononstabilityandactivityofantitumorpeptiderdp215againsthumanmelanomaandglioblastoma AT sabrinariedl effectofltodaminoacidsubstitutiononstabilityandactivityofantitumorpeptiderdp215againsthumanmelanomaandglioblastoma AT beaterinner effectofltodaminoacidsubstitutiononstabilityandactivityofantitumorpeptiderdp215againsthumanmelanomaandglioblastoma AT dagmarzweytick effectofltodaminoacidsubstitutiononstabilityandactivityofantitumorpeptiderdp215againsthumanmelanomaandglioblastoma |