Structure-based design, synthesis and evaluation of a novel family of PEX5-PEX14 interaction inhibitors against Trypanosoma

Napolitano, Valeria; Mróz, Piotr; Marciniak, Monika; Kalel, Vishal C.; Softley, Charlotte A.; Janna Olmos, Julian D.; Tippler, Bettina G.; Schorpp, Kenji; Rioton, Sarah; Fröhlich, Tony; Plettenburg, Oliver; Hadian, Kamyar; Erdmann, Ralf; Sattler, Michael; Popowicz, Grzegorz M.; Dawidowski, Maciej; Dubin, Grzegorz

Abstract

Trypanosomiases are neglected tropical diseases caused by Trypanosoma (sub)species. Available treatments are limited and have considerable adverse effects and questionable efficacy in the chronic stage of the disease, urgently calling for the identification of new targets and drug candidates.
Recently, we have shown that impairment of glycosomal protein import by the inhibition of the PEX5-PEX14 protein-protein interaction (PPI) is lethal to Trypanosoma. Here, we report the development of a novel dibenzo[b,f][1,4]oxazepin-11(10H)-one scaffold for small molecule inhibitors of PEX5-PEX14 PPI. The initial hit was identified by a high throughput screening (HTS) of a library of compounds. A bioisosteric replacement approach allowed to replace the metabolically unstable sulphur atom from the initial dibenzo[b,f][1,4]thiazepin-11(10H)-one HTS hit with oxygen. A crystal structure of the hit compound bound to PEX14 surface facilitated the rational design of the compound series accessible by a straightforward chemistry for the initial structure-activity relationship (SAR) analysis. This guided the design of compounds with trypanocidal activity in cell-based assays providing a promising starting point for the development of new drug candidates to tackle trypanosomiases.

Citation

Napolitano, V., Mróz, P., Marciniak, M., Kalel, V. C., Softley, C. A., Janna Olmos, J. D., Tippler, B. G., Schorpp, K., Rioton, S., Fröhlich, T., Plettenburg, O., Hadian, K., Erdmann, R., Sattler, M., Popowicz, G. M., Dawidowski, M., & Dubin, G. (2022). Structure-based design, synthesis and evaluation of a novel family of PEX5-PEX14 interaction inhibitors against Trypanosoma. European Journal of Medicinal Chemistry, 243, Article 114778. https://doi.org/10.1016/j.ejmech.2022.114778

• Journal Article Type: Article
• Acceptance Date: Sep 13, 2022
• Publication Date: 2022-12
• Deposit Date: Feb 24, 2025
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 243
• Article Number: 114778
• DOI: https://doi.org/10.1016/j.ejmech.2022.114778
• Public URL: https://keele-repository.worktribe.com/output/1078848
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523422006808
• Additional Information: This article is maintained by: Elsevier; Article Title: Structure-based design, synthesis and evaluation of a novel family of PEX5-PEX14 interaction inhibitors against Trypanosoma; Journal Title: European Journal of Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ejmech.2022.114778; Content Type: article; Copyright: © 2022 The Authors. Published by Elsevier Masson SAS.