Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14-3-3 Protein-Protein Interactions

Angewandte Chemie
Sebastian A AndreiYusuke Higuchi

Abstract

The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X-ray crystallography confirmed the power of the MD-based design approach, revealing the potential for an additional hydrogen bond with the 14-3-3 protein to lead to significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small-molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization.

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Citations

Nov 24, 2018·Planta·Lorenzo CamoniMauro Marra
May 30, 2019·Future Medicinal Chemistry·Kanin WichapongGerry Af Nicolaes
Oct 3, 2020·Acta Crystallographica. Section F, Structural Biology Communications·Alice BalloneChristian Ottmann
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Dec 10, 2019·MedChemComm·Dario ValentiChristian Ottmann
Aug 21, 2020·Angewandte Chemie·Madita WolterChristian Ottmann
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Sep 2, 2020·European Journal of Medicinal Chemistry·Yuran QiuShaoyong Lu
Jun 6, 2020·Journal of the American Chemical Society·Madita WolterChristian Ottmann
Jun 18, 2021·ACS Medicinal Chemistry Letters·Eline SijbesmaChristian Ottmann
Nov 4, 2020·Journal of Chemical Information and Modeling·Alice BalloneMattia Mori
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan
Jun 6, 2020·Journal of Medicinal Chemistry·Xavier GuilloryChristian Ottmann

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