3 research outputs found
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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-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
Recommended from our members
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-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
Functional variability of novel CDC42 pathogenic variants is associated with phenotypic heterogeneity of neurodevelopmental and immune-hematologic related disorders
CDC42 (Cell Division Cycle 42) is a small GTPase of the RAS super family regulating key developmental processes. We have recently characterized different CDC42 missense mutations associated with a broad spectrum of immune-haematological and neurodevelopmental disorders, which include RASopathies-related phenotypes.
Here, we report the identification and molecular characterization of six additional CDC42 variants (p.K16R, p.Y23H, p.P34L, p.D118G, p.G164R, and p.D170N) associated with neurodevelopmental and immune-haematological conditions. In particular, patients present with various degree of cardiac defects, neurodevelopmental delay, facial dysmorphisms, and recurrent infections. CDC42 mutants variably affect protein expression and localization (Fig. 1) , GTPase activity (Fig. 2A), effector binding (i.e. RHOGDI (Fig. 2B), IQGAP1 (Fig. 3A), N-WASP (Fig. 3B), and, and RAS-mitogen-activated protein kinase (MAPK) pathway (Fig. 4). The comparative functional analysis of the CDC42 variants so far described indicates that only the IQGAP1-binding defective CDC42 mutants are associated with the immune-hematologic phenotype, suggesting a common pathogenic mechanism for these variants. Moreover, the majority of CDC42 variants significantly increases MAPK activation, indicating a role of the RAS-MAPK pathway in the pathogenesis of CDC42-associated disorders. Finally, our study expands the spectrum of CDC42 pathogenic variants and confirms the relevance of functional validation of unclassified variants to assess their possible role in disease pathogenicity