Details
| Original language | English |
|---|---|
| Article number | 115587 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 258 |
| Early online date | 25 Jun 2023 |
| Publication status | Published - 5 Oct 2023 |
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
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
- Chemistry(all)
- Organic Chemistry
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In: European Journal of Medicinal Chemistry, Vol. 258, 115587, 05.10.2023.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
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
N1 - Funding Information: This study has been funded by Narodowe Centrum Nauki (grant UMO-2016/23/B/NZ7/03339 to M.D., M.M. and P.M.), Deutsche Forschungsgemeinschaft (grant FOR1905 to M.S. and R.E.) and by Bundesministerium für Bildung and Forschung (grant PEXMED to G.P., M.S. and R.E).
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.
KW - Oxopiperazine
KW - Peptidomimetics
KW - Protein-protein interaction inhibitors
KW - Structure-based drug design
KW - Trypanocidal inhibitors
KW - α-Helical mimetics
UR - http://www.scopus.com/inward/record.url?scp=85163819403&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2023.115587
DO - 10.1016/j.ejmech.2023.115587
M3 - Article
C2 - 37406382
AN - SCOPUS:85163819403
VL - 258
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 115587
ER -