Molecular Tweezers Inhibit PARP‐1 by a New Mechanism

Wilch, Constanze; Talbiersky, Peter; Berchner‐Pfannschmidt, Utta; Schaller, Torsten; Kirsch, Michael; Klärner, Frank‐Gerrit; Schräder, Thomas

doi:10.1002/ejoc.201601596

Cited by 7 publications

(13 citation statements)

References 35 publications

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“…Those lysine residues located the edge of the amphipathic groove of 14-3-3σ can form inclusion complexes with the tweezer so that the space of groove will be changed to affect the activity of the chaperone protein 14-3-3σ. Thus, the partner proteins are inactivated either by cofactor capture or by complexation with lysine residues, most likely in the vicinity of the active site, which shows for the III-type lysine residues (Wilch et al, 2017). According to the crystal structure of 14-3-3/ExoS (Ottmann et al, 2007b; Karlberg et al, 2018) and tweezer/K214 (Bier et al, 2013), we can find that the C-terminal of the ExoS is occupied at the same position for tweezer, which further indicates that the 14-3-3/ExoS PPI system could be disrupted by the tweezer molecule and result in the loss of activity of ExoS.…”

Section: Resultsmentioning

confidence: 99%

“…This phenomenon is not unique. A recent study for the interactions between CLR01 and poly[ADP-ribose]polymerase (PARP-1) also show distinct multiple lysine recognition site (Wilch et al, 2017). More interestingly, such a recognition ability of CLR01 was considered to be an efficient inhibition method.…”

Section: Discussionmentioning

confidence: 99%

“…The function of this inhibitor is versatile, e.g., regulating the aggregation of α-synuclein (Acharya et al, 2014), modulating the aggregation propensity and cytotoxicity of huntingtin protein (Vöpel et al, 2017), and inhibiting the activity of PARP-1(Wilch et al, 2017). The tweezer molecule is a water-soluble belt-like molecule with a torus-shaped cavity surrounded by alternating aromatic and aliphatic rings, which has the specificity of recognizing either lysine or arginine.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism

Shi

2019

Front. Chem.

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The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify protein functions. As one of the more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-protein interactions. In this work, we selected 14-3-3σ as the target protein. Molecular dynamics simulations and binding free energy calculations were applied to identify the possible binding sites and understand its recognition ability of the supramolecular inhibitor, the tweezer molecule (CLR01). On the basis of our simulation, major interactions between lysine residues and CLR01 come from the van der Waals interactions between the long alkyl chain of lysine and the cavity formed by the norbornadiene and benzene rings of the inhibitor. Apart from K214, which was found to be crystallized with this inhibitor, other lysine sites have also shown their abilities to form inclusion complexes with the inhibitor. Such non-specific recognition features of CLR01 against 14-3-3σ can be used in the modification of protein functions via supramolecular chemistry.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism

Shi

2019

Front. Chem.

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“…Two (hydrogen)phosphate groups lock the included side chain in an ion pair 29 . This unique binding mechanism operates well under physiological conditions and has already been exploited for protease inhibition 30 , 31 , prevention of protein aggregation 32 , 33 , and modulation of PPIs on shallow grooves 7 , 34 . In order to turn these molecular tools into specific Survivin ligands, it was necessary to identify a binding motif for the NES region and to develop a synthesis for efficient tweezer monofunctionalization.…”

Section: Introductionmentioning

confidence: 99%

Specific inhibition of the Survivin–CRM1 interaction by peptide-modified molecular tweezers

et al. 2021

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Survivin’s dual function as apoptosis inhibitor and regulator of cell proliferation is mediated via its interaction with the export receptor CRM1. This protein–protein interaction represents an attractive target in cancer research and therapy. Here, we report a sophisticated strategy addressing Survivin’s nuclear export signal (NES), the binding site of CRM1, with advanced supramolecular tweezers for lysine and arginine. These were covalently connected to small peptides resembling the natural, self-complementary dimer interface which largely overlaps with the NES. Several biochemical methods demonstrated sequence-selective NES recognition and interference with the critical receptor interaction. These data were strongly supported by molecular dynamics simulations and multiscale computational studies. Rational design of lysine tweezers equipped with a peptidic recognition element thus allowed to address a previously unapproachable protein surface area. As an experimental proof-of-principle for specific transport signal interference, this concept should be transferable to any protein epitope with a flanking well-accessible lysine.

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“…Phosphate molecular clip and tweezers developed by Klärner and their applications as enzyme inhibitors, illustrated by the alcohol dehydrogenase (ADH), protein aggregation inhibitors illustrated by amyloid β (Aβ) fibril aggregation, protein-protein interaction modulator and antiviral agent. Adapted from [54,55]. …”

Section: Figurementioning

confidence: 99%

Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

2019

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Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools.

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Molecular Tweezers Inhibit PARP‐1 by a New Mechanism

Cited by 7 publications

References 35 publications

Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism

Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism

Specific inhibition of the Survivin–CRM1 interaction by peptide-modified molecular tweezers

Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

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