Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template

Monika Marciniak; Piotr Mróz; Valeria Napolitano; Vishal C. Kalel; Roberto Fino; Emilia Pykacz; Wolfgang Schliebs; Oliver Plettenburg; Ralf Erdmann; Michael Sattler; Grzegorz M. Popowicz; Maciej Dawidowski

doi:10.1016/j.ejmech.2023.115587

Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template

Monika Marciniak, Piotr Mróz, Valeria Napolitano, Vishal C. Kalel, Roberto Fino, Emilia Pykacz, Wolfgang Schliebs, Oliver Plettenburg, Ralf Erdmann, Michael Sattler, Grzegorz M. Popowicz, Maciej Dawidowski

Chair of Biomolecular NMR-Spectroscopy

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Protein-protein interactions (PPIs) constitute an important but challenging class of molecular targets for small molecules. The PEX5-PEX14 PPI has been shown to play a critical role in glycosome biogenesis and its disruption impairs the metabolism in Trpanosoma parasites, eventually leading to their death. Therefore, this PPI is a potential molecular target for new drugs against diseases caused by Trypanosoma infections. Here, we report a new class of peptidomimetic scaffolds to target the PEX5-PEX14 PPI. The molecular design was based on an oxopiperazine template for the α-helical mimetics. A structural simplification along with modifications of the central oxopiperazine scaffold and addressing the lipophilic interactions led to the development of peptidomimetics that inhibit PEX5-TbPEX14 PPI and display cellular activity against T. b. brucei. This approach provides an alternative approach towards the development of trypanocidal agents and may be generally useful for the design of helical mimetics as PPI inhibitors.

Original language	English
Article number	115587
Journal	European Journal of Medicinal Chemistry
Volume	258
DOIs	https://doi.org/10.1016/j.ejmech.2023.115587
State	Published - 5 Oct 2023

Keywords

Oxopiperazine
Peptidomimetics
Protein-protein interaction inhibitors
Structure-based drug design
Trypanocidal inhibitors
α-Helical mimetics

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10.1016/j.ejmech.2023.115587

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Marciniak, M., Mróz, P., Napolitano, V., Kalel, V. C., Fino, R., Pykacz, E., Schliebs, W., Plettenburg, O., Erdmann, R., Sattler, M., Popowicz, G. M., & Dawidowski, M. (2023). Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template. European Journal of Medicinal Chemistry, 258, Article 115587. https://doi.org/10.1016/j.ejmech.2023.115587

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title = "Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template",

abstract = "Protein-protein interactions (PPIs) constitute an important but challenging class of molecular targets for small molecules. The PEX5-PEX14 PPI has been shown to play a critical role in glycosome biogenesis and its disruption impairs the metabolism in Trpanosoma parasites, eventually leading to their death. Therefore, this PPI is a potential molecular target for new drugs against diseases caused by Trypanosoma infections. Here, we report a new class of peptidomimetic scaffolds to target the PEX5-PEX14 PPI. The molecular design was based on an oxopiperazine template for the α-helical mimetics. A structural simplification along with modifications of the central oxopiperazine scaffold and addressing the lipophilic interactions led to the development of peptidomimetics that inhibit PEX5-TbPEX14 PPI and display cellular activity against T. b. brucei. This approach provides an alternative approach towards the development of trypanocidal agents and may be generally useful for the design of helical mimetics as PPI inhibitors.",

keywords = "Oxopiperazine, Peptidomimetics, Protein-protein interaction inhibitors, Structure-based drug design, Trypanocidal inhibitors, α-Helical mimetics",

author = "Monika Marciniak and Piotr Mr{\'o}z and Valeria Napolitano and Kalel, {Vishal C.} and Roberto Fino and Emilia Pykacz and Wolfgang Schliebs and Oliver Plettenburg and Ralf Erdmann and Michael Sattler and Popowicz, {Grzegorz M.} and Maciej Dawidowski",

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Marciniak, M, Mróz, P, Napolitano, V, Kalel, VC, Fino, R, Pykacz, E, Schliebs, W, Plettenburg, O, Erdmann, R, Sattler, M, Popowicz, GM & Dawidowski, M 2023, 'Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template', European Journal of Medicinal Chemistry, vol. 258, 115587. https://doi.org/10.1016/j.ejmech.2023.115587

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T1 - Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template

AU - Marciniak, Monika

AU - Mróz, Piotr

AU - Napolitano, Valeria

AU - Kalel, Vishal C.

AU - Fino, Roberto

AU - Pykacz, Emilia

AU - Schliebs, Wolfgang

AU - Plettenburg, Oliver

AU - Erdmann, Ralf

AU - Sattler, Michael

AU - Popowicz, Grzegorz M.

AU - Dawidowski, Maciej

PY - 2023/10/5

Y1 - 2023/10/5

N2 - Protein-protein interactions (PPIs) constitute an important but challenging class of molecular targets for small molecules. The PEX5-PEX14 PPI has been shown to play a critical role in glycosome biogenesis and its disruption impairs the metabolism in Trpanosoma parasites, eventually leading to their death. Therefore, this PPI is a potential molecular target for new drugs against diseases caused by Trypanosoma infections. Here, we report a new class of peptidomimetic scaffolds to target the PEX5-PEX14 PPI. The molecular design was based on an oxopiperazine template for the α-helical mimetics. A structural simplification along with modifications of the central oxopiperazine scaffold and addressing the lipophilic interactions led to the development of peptidomimetics that inhibit PEX5-TbPEX14 PPI and display cellular activity against T. b. brucei. This approach provides an alternative approach towards the development of trypanocidal agents and may be generally useful for the design of helical mimetics as PPI inhibitors.

AB - Protein-protein interactions (PPIs) constitute an important but challenging class of molecular targets for small molecules. The PEX5-PEX14 PPI has been shown to play a critical role in glycosome biogenesis and its disruption impairs the metabolism in Trpanosoma parasites, eventually leading to their death. Therefore, this PPI is a potential molecular target for new drugs against diseases caused by Trypanosoma infections. Here, we report a new class of peptidomimetic scaffolds to target the PEX5-PEX14 PPI. The molecular design was based on an oxopiperazine template for the α-helical mimetics. A structural simplification along with modifications of the central oxopiperazine scaffold and addressing the lipophilic interactions led to the development of peptidomimetics that inhibit PEX5-TbPEX14 PPI and display cellular activity against T. b. brucei. This approach provides an alternative approach towards the development of trypanocidal agents and may be generally useful for the design of helical mimetics as PPI inhibitors.

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KW - Peptidomimetics

KW - Protein-protein interaction inhibitors

KW - Structure-based drug design

KW - Trypanocidal inhibitors

KW - α-Helical mimetics

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JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 115587

ER -

Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template

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