Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs
Abstract Background Over the last years, several strategies have been reported to improve the metabolic stability of minigastrin analogs. However, currently applied compounds still reveal limited in vitro and in vivo stability. We thus performed a glycine scan at the N-terminus of DOTA-MGS5 (DOTA-d-...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2023-07-01
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| Series: | EJNMMI Research |
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| Online Access: | https://doi.org/10.1186/s13550-023-01016-y |
| _version_ | 1797784444563619840 |
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| author | Nadine Holzleitner Thomas Günther Amira Daoud-Gadieh Constantin Lapa Hans-Jürgen Wester |
| author_facet | Nadine Holzleitner Thomas Günther Amira Daoud-Gadieh Constantin Lapa Hans-Jürgen Wester |
| author_sort | Nadine Holzleitner |
| collection | DOAJ |
| description | Abstract Background Over the last years, several strategies have been reported to improve the metabolic stability of minigastrin analogs. However, currently applied compounds still reveal limited in vitro and in vivo stability. We thus performed a glycine scan at the N-terminus of DOTA-MGS5 (DOTA-d-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal) to systematically analyze the peptide structure. We substituted N-terminal amino acids by simple PEG spacers and investigated in vitro stability in human serum. Furthermore, we evaluated different modifications on its tetrapeptide binding sequence (H-Trp-(N-Me)Nle-Asp-1-Nal-NH2). Results Affinity data of all glycine scan peptides were found to be in a low nanomolar range (4.2–8.5 nM). However, a truncated compound lacking the d-γ-Glu-Ala-Tyr sequence revealed a significant loss in CCK-2R affinity. Substitution of the d-γ-Glu-Ala-Tyr-Gly sequence of DOTA-γ-MGS5 (DOTA- d-γ-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH2) by polyethylene glycol (PEG) spacers of different length exhibited only a minor influence on CCK-2R affinity and lipophilicity. However, in vitro stability of the PEG-containing compounds was significantly decreased. In addition, we confirmed that the tetrapeptide sequence H-Trp-Asp-(N-Me)Nle-1-Nal-NH2 is indeed sufficient for high CCK-2R affinity. Conclusion We could demonstrate that a substitution of d-γ-Glu-Ala-Tyr-Gly by PEG spacers simplified the peptide structure of DOTA-MGS5 while high CCK-2R affinity and favorable lipophilicity were maintained. Nevertheless, further optimization with regard to metabolic stability must be carried out for these minigastrin analogs. |
| first_indexed | 2024-03-13T00:39:57Z |
| format | Article |
| id | doaj.art-b2cf2f4f6b9c494c9c68d658fa804ed7 |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-03-13T00:39:57Z |
| publishDate | 2023-07-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-b2cf2f4f6b9c494c9c68d658fa804ed72023-07-09T11:24:49ZengSpringerOpenEJNMMI Research2191-219X2023-07-011311810.1186/s13550-023-01016-yInvestigation of the structure-activity relationship at the N-terminal part of minigastrin analogsNadine Holzleitner0Thomas Günther1Amira Daoud-Gadieh2Constantin Lapa3Hans-Jürgen Wester4Department of Chemistry, Technical University of MunichDepartment of Chemistry, Technical University of MunichDepartment of Chemistry, Technical University of MunichNuclear Medicine, University Hospital AugsburgDepartment of Chemistry, Technical University of MunichAbstract Background Over the last years, several strategies have been reported to improve the metabolic stability of minigastrin analogs. However, currently applied compounds still reveal limited in vitro and in vivo stability. We thus performed a glycine scan at the N-terminus of DOTA-MGS5 (DOTA-d-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal) to systematically analyze the peptide structure. We substituted N-terminal amino acids by simple PEG spacers and investigated in vitro stability in human serum. Furthermore, we evaluated different modifications on its tetrapeptide binding sequence (H-Trp-(N-Me)Nle-Asp-1-Nal-NH2). Results Affinity data of all glycine scan peptides were found to be in a low nanomolar range (4.2–8.5 nM). However, a truncated compound lacking the d-γ-Glu-Ala-Tyr sequence revealed a significant loss in CCK-2R affinity. Substitution of the d-γ-Glu-Ala-Tyr-Gly sequence of DOTA-γ-MGS5 (DOTA- d-γ-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH2) by polyethylene glycol (PEG) spacers of different length exhibited only a minor influence on CCK-2R affinity and lipophilicity. However, in vitro stability of the PEG-containing compounds was significantly decreased. In addition, we confirmed that the tetrapeptide sequence H-Trp-Asp-(N-Me)Nle-1-Nal-NH2 is indeed sufficient for high CCK-2R affinity. Conclusion We could demonstrate that a substitution of d-γ-Glu-Ala-Tyr-Gly by PEG spacers simplified the peptide structure of DOTA-MGS5 while high CCK-2R affinity and favorable lipophilicity were maintained. Nevertheless, further optimization with regard to metabolic stability must be carried out for these minigastrin analogs.https://doi.org/10.1186/s13550-023-01016-yCholecystokinin-2 receptor (CCK-2R)Cholecystokinin-B receptor (CCK-BR)Medullary thyroid carcinoma (MTC)MinigastrinTetrapeptide |
| spellingShingle | Nadine Holzleitner Thomas Günther Amira Daoud-Gadieh Constantin Lapa Hans-Jürgen Wester Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs EJNMMI Research Cholecystokinin-2 receptor (CCK-2R) Cholecystokinin-B receptor (CCK-BR) Medullary thyroid carcinoma (MTC) Minigastrin Tetrapeptide |
| title | Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs |
| title_full | Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs |
| title_fullStr | Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs |
| title_full_unstemmed | Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs |
| title_short | Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs |
| title_sort | investigation of the structure activity relationship at the n terminal part of minigastrin analogs |
| topic | Cholecystokinin-2 receptor (CCK-2R) Cholecystokinin-B receptor (CCK-BR) Medullary thyroid carcinoma (MTC) Minigastrin Tetrapeptide |
| url | https://doi.org/10.1186/s13550-023-01016-y |
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