The Pseudo‐Natural Product Rhonin Targets RHOGDI

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment‐base...

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Published in:Angewandte Chemie 2022-04, Vol.134 (18), p.n/a
Main Authors: Akbarzadeh, Mohammad, Flegel, Jana, Patil, Sumersing, Shang, Erchang, Narayan, Rishikesh, Buchholzer, Marcel, Kazemein Jasemi, Neda S., Grigalunas, Michael, Krzyzanowski, Adrian, Abegg, Daniel, Shuster, Anton, Potowski, Marco, Karatas, Hacer, Karageorgis, George, Mosaddeghzadeh, Niloufar, Zischinsky, Mia‐Lisa, Merten, Christian, Golz, Christopher, Brieger, Lucas, Strohmann, Carsten, Antonchick, Andrey P., Janning, Petra, Adibekian, Alexander, Goody, Roger S., Ahmadian, Mohammad Reza, Ziegler, Slava, Waldmann, Herbert
Format: Article
Language:English
Subjects:
Biological activity
Chemistry
Enantiomers
Inhibitors
Liposomes
Localization
Natural products
Osteogenesis
Proteins
Pseudo-Natural Products
RHOGDI
Small Molecules
Target recognition
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Summary:For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment‐based design. We describe the de novo combination of different 5‐membered NP‐derived N‐heteroatom fragments to structurally unprecedented “pseudo‐natural products” in an efficient complexity‐generating and enantioselective one‐pot synthesis sequence. The pseudo‐NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP‐derived chemotypes, and may have novel biological targets. Investigation of the pseudo‐NPs in unbiased phenotypic assays and target identification led to the discovery of the first small‐molecule ligand of the RHO GDP‐dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP‐bound RHO GTPases and alters the subcellular localization of RHO GTPases. The identification of the pseudo‐natural product Rhonin as the first small‐molecule modulator of RHO GDP dissociation inhibitor (RHOGDI) is reported. Rhonin binds to RHOGDI and interferes with its function by disrupting the interaction between RHOGDI and RHO GTPases.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202115193