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Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs

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-...

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Autores principales: Holzleitner, Nadine, Günther, Thomas, Daoud-Gadieh, Amira, Lapa, Constantin, Wester, Hans-Jürgen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10329608/
https://www.ncbi.nlm.nih.gov/pubmed/37421545
http://dx.doi.org/10.1186/s13550-023-01016-y
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author Holzleitner, Nadine
Günther, Thomas
Daoud-Gadieh, Amira
Lapa, Constantin
Wester, Hans-Jürgen
author_facet Holzleitner, Nadine
Günther, Thomas
Daoud-Gadieh, Amira
Lapa, Constantin
Wester, Hans-Jürgen
author_sort Holzleitner, Nadine
collection PubMed
description 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-NH(2)). 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-NH(2)) 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-NH(2) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-023-01016-y.
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spelling pubmed-103296082023-07-10 Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs Holzleitner, Nadine Günther, Thomas Daoud-Gadieh, Amira Lapa, Constantin Wester, Hans-Jürgen EJNMMI Res Original Research 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-NH(2)). 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-NH(2)) 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-NH(2) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-023-01016-y. Springer Berlin Heidelberg 2023-07-08 /pmc/articles/PMC10329608/ /pubmed/37421545 http://dx.doi.org/10.1186/s13550-023-01016-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Research
Holzleitner, Nadine
Günther, Thomas
Daoud-Gadieh, Amira
Lapa, Constantin
Wester, Hans-Jürgen
Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs
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 Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10329608/
https://www.ncbi.nlm.nih.gov/pubmed/37421545
http://dx.doi.org/10.1186/s13550-023-01016-y
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