Direct Modulation of Small GTPase Activity and Function

Cromm, Philipp M.; Spiegel, Jochen; Grossmann, Tom N.; Waldmann, Herbert

doi:10.1002/anie.201504357

Cited by 68 publications

(70 citation statements)

References 212 publications

(259 reference statements)

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“…56 However, effective and bioavailable inhibitors of Rab GTPases have not been identified thus far. 3,5,12 Notable, the stapled peptide StRIP3 has been described as the first inhibitor of a Rab PPI in vitro. 4 vi) Replacement of negatively charged residues to promote cellular uptake.…”

Section: Discussionmentioning

confidence: 99%

“…A reason for the difficulties in targeting GTPases with small molecules is the engagement of these proteins in numerous intracellular protein-protein interactions (PPI) which are often not susceptible to traditional small molecule-based approaches. [2][3][4][5] Rab GTPases are master regulators of intracellular trafficking and vesicular transport and represent the largest subfamily of small GTPases. [6][7][8] Members of this subfamily are implicated in a number of human diseases rendering them attractive targets in drug discovery [9][10][11] with only few synthetic modulators of activity reported so far.…”

Section: Introductionmentioning

confidence: 99%

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Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

et al. 2016

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Small GTPases comprise a family of highly relevant targets in chemical biology and medicinal chemistry research and have been considered "undruggable" due to the persisting lack of effective synthetic modulators and suitable binding pockets. As molecular switches, small GTPases control a multitude of pivotal cellular functions, and their dysregulation is associated with many human diseases such as various forms of cancer. Rab-GTPases represent the largest subfamily of small GTPases and are master regulators of vesicular transport interacting with various proteins via flat and extensive protein-protein interactions (PPIs). The only reported synthetic inhibitor of a PPI involving an activated Rab GTPase is the hydrocarbon stapled peptide StRIP3. However, this macrocyclic peptide shows low proteolytic stability and cell permeability. Here, we report the design of a bioavailable StRIP3 analogue that harbors two hydrophobic cross-links and exhibits increased binding affinity, combined with robust cellular uptake and extremely high proteolytic stability. Localization experiments reveal that this double-stapled peptide and its target protein Rab8a accumulate in the same cellular compartments. The reported approach offers a strategy for the implementation of biostability into conformationally constrained peptides while supporting cellular uptake and target affinity, thereby conveying drug-like properties.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

et al. 2016

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“…These molecules function in many distinct and important cellular processes, including signal transduction in conjugation with the intracellular domain of transmembrane receptors, protein biosynthesis, cell cycle kinetics and differentiation, macroautophagy, vesicle transport, and protein translocation through membranes. [1][2][3][4][5] Abnormal GTPase activities are significant in the etiology of many human diseases. [6][7][8] In mammalian oocytes, many members of GTPase superfamily have been identified to be involved in meiosis progression.…”

Section: Introductionmentioning

confidence: 99%

GTPase-activating protein Elmod2 is essential for meiotic progression in mouse oocytes

Zhou

Shi

et al. 2017

Cell Cycle

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Meiotic failure in oocytes is the major determinant of human zygote-originated reproductive diseases, the successful accomplishment of meiosis largely relay on the normal functions of many female fertility factors. Elmod2 is a member of the Elmod family with the strongest GAP (GTPase-activating protein) activity; although it was identified as a possible maternal protein, its actual physiologic role in mammalian oocytes has not been elucidated. Herein we reported that among Elmod family proteins, Elmod2 is the most abundant in mouse oocytes, and that inhibition of Elmod2 by specific siRNA caused severe meiotic delay and abnormal chromosomal segregation during anaphase. Elmod2 knockdown also significantly decreased the rate of oocyte maturation (to MII, with first polar body extrusion), and significantly greater numbers of Elmod2-knockdown MII oocytes were aneuploid. Correspondingly, Elmod2 knockdown dramatically decreased fertilization rate. To investigate the mechanism(s) involved, we found that Elmod2 knockdown caused significantly more abnormal mitochondrial aggregation and diminished cellular ATP levels; and we also found that Elmod2 co-localized and interacted with Arl2, a GTPase that is known to maintain mitochondrial dynamics and ATP levels in oocytes. In summary, we found that Elmod2 is the GAP essential to meiosis progression of mouse oocytes, most likely by regulating mitochondrial dynamics.

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“…39,96–98 However, apart from thiol-reactive agents that covalently modify the mutant cysteine of G12C K-Ras, 76,99–101 the remaining candidates cannot be differentiated between the target oncogenic mutant Ras and the wild-type (WT) Ras, leading to the inhibition of both oncogenic and WT Ras. This effect has the potential to cause significant toxic side effects.…”

Section: Nucleotides and Oncogenic Mutations Affect The Conformatiomentioning

confidence: 99%

Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

et al. 2016

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Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras–effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins.

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Direct Modulation of Small GTPase Activity and Function

Cited by 68 publications

References 212 publications

Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

GTPase-activating protein Elmod2 is essential for meiotic progression in mouse oocytes

Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

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