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The Pseudo-Natural Product Rhonin Targets RHOGDI.

Mohammad Akbarzadeh^1,2, Jana Flegel¹, Sumersing Patil¹

¹Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.

Angewandte Chemie (International Ed. in English)

|February 16, 2022

Summary

This summary is machine-generated.

Researchers created novel pseudo-natural products by combining natural product fragments. This led to the discovery of Rhonin, the first small-molecule ligand for RHO GDP-dissociation inhibitor 1 (RHOGDI1), impacting RHO GTPase localization.

Keywords:

Inhibitors Liposomes Osteogenesis Proteins Pseudo-Natural Products RHOGDI Small Molecules

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Area of Science:

Medicinal Chemistry
Chemical Biology
Drug Discovery

Background:

Natural products (NPs) offer valuable scaffolds for bioactive compound discovery.
Fragment-based design and de novo synthesis are powerful strategies for exploring chemical space.
Identifying novel ligands for protein regulators like RHOGDI1 is crucial for understanding cellular processes.

Purpose of the Study:

To develop a novel synthetic strategy for creating structurally unprecedented pseudo-natural products (pseudo-NPs) from natural product-derived fragments.
To explore the biological activity of these pseudo-NPs through unbiased phenotypic screening.
To identify the molecular target of any bioactive pseudo-NPs discovered.

Main Methods:

De novo synthesis combining 5-membered N-heteroatom fragments derived from natural products.
Enantioselective one-pot reaction sequences for efficient complexity generation.
Unbiased phenotypic assays and target identification techniques.

Main Results:

Synthesis of structurally unique pseudo-NPs with inherited NP characteristics but novel chemical space coverage.
Discovery of Rhonin, the first small-molecule ligand for RHO GDP-dissociation inhibitor 1 (RHOGDI1).
Rhonin was shown to inhibit RHOGDI1 chaperone binding to GDP-bound RHO GTPases and alter RHO GTPase subcellular localization.

Conclusions:

The combination of NP-derived fragments offers an efficient route to novel chemical matter with potential for new biological targets.
Rhonin represents a significant advancement in targeting the RHOGDI1-RHO GTPase interaction, providing a tool to study RHO GTPase regulation.
This approach expands the accessible chemical space beyond traditional natural product chemotypes, facilitating drug discovery.