The Pseudo‐Natural Product Rhonin Targets RHOGDI

Abstract

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.

Yersinia entomophaga Tc toxin is released by T10SS-dependent lysis of specialized cell subpopulations

“…All experiments were carried out with at least 3 independent biological replicates. No statistical methods were used to pre-determine sample sizes but our sample sizes for each type of experiment are similar to those reported in previous publications 91 – 94 . Data distribution normality and equal variances were formally tested using Shapiro–Wilk and F -tests, respectively.…”

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

“…The pseudo-NPs may inherit the biological relevance of NPs, however, their structures are not yet linked to bioactivity which may lead to the identification of unexpected [10][11][12] or unprecedented bioactivities. [13] We describe the design and synthesis of a focused pseudo-NP collection comprised of two classes representing unprecedented scaffolds that occupy similar biologically relevant chemical space as MIA NPs (Figure 1b). In these pseudo-NPs, the high structural and spatial complexity, characteristic for the MIAs, is kept as a decisive design element.…”

“…According to this design principle, NPs are deconstructed into fragments and recombined in arrangements that are not found in Nature to afford scaffolds that are NP‐like but are not accessible via known biosynthetic pathways. The pseudo‐NPs may inherit the biological relevance of NPs, however, their structures are not yet linked to bioactivity which may lead to the identification of unexpected [10–12] or unprecedented bioactivities [13] …”

Unprecedented Combination of Polyketide Natural Product Fragments Identifies the New Hedgehog Signaling Pathway Inhibitor Grismonone

“…Accordingly, pseudo-NP collections may explore new regions of biologically relevant chemical space and be enriched with unexpected and/or novel bioactivities. [11][12][13][14][15][16][17][18][19][20] This concept may be considered the synthetic analogue of recombination of existing biosynthetic pathways to access novel NP-like scaffolds, and, thereby, a chemical equivalent to natural evolution of NP structure. [10] Previous pseudo-NP designs and syntheses were guided by the principle to combine fragments from biosynthetically unrelated NPs to guarantee structural novelty and, in extension, also novel bioactivity.…”

“…We have proposed the design principle of pseudo‐natural products [8–10] (pseudo‐NPs) in which biosynthetically unrelated NP fragments or fragment‐sized NPs are combined to afford scaffolds that resemble NPs but are not accessible through existing biosynthetic pathways. Accordingly, pseudo‐NP collections may explore new regions of biologically relevant chemical space and be enriched with unexpected and/or novel bioactivities [11–20] . This concept may be considered the synthetic analogue of recombination of existing biosynthetic pathways to access novel NP‐like scaffolds, and, thereby, a chemical equivalent to natural evolution of NP structure [10] …”