Host–guest chemistry that directly targets lysine methylation: synthetic host molecules as alternatives to bio-reagents

Hof, Fraser

doi:10.1039/c6cc04771h

Cited by 51 publications

(30 citation statements)

References 86 publications

(178 reference statements)

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“…Though excellent selectivities for a specific group type are possible, differentiating identical modifications at different positions is extremely challenging, especially under the conditions of an enzyme assay. CX 11 and cyclophane 9f,g,12 sensors are capable of selectively recognizing lysine and arginine methylations, and array-based versions can distinguish methylations at different positions on modified peptide substrates. 13 These techniques have not yet been coupled to an enzyme assay, though.…”

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confidence: 99%

Site-Selective Sensing of Histone Methylation Enzyme Activity via an Arrayed Supramolecular Tandem Assay

et al. 2017

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Arrayed deep cavitands can be coupled to a fluorescence-based supramolecular tandem assay that allows site-selective in situ monitoring of post-translational modifications catalyzed by the lysine methyltransferase PRDM9 or the lysine demethylase JMJD2E. An arrayed sensor system containing only three cavitand components can detect the specific substrates of enzyme modification, in the presence of other histone peptides in the enzyme assay, enabling investigation of cross-reactivity over multiple methylation sites and interference from non-substrate peptides.

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confidence: 99%

Site-Selective Sensing of Histone Methylation Enzyme Activity via an Arrayed Supramolecular Tandem Assay

et al. 2017

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“…Our approach involved the use of sulfonatocalix [4]arenes that are also strong cation binders in water. [10,11] These calixarenes were decorated with asubstituent containing ahydroxamic acid, which is known to detoxify OPs. [12,13] Synthesis involved the coupling of monoamine 1 [11a] to carboxylic acids with ap rotected hydroxamic acid.…”

mentioning

confidence: 99%

Detoxification of VX and Other V‐Type Nerve Agents in Water at 37 °C and pH 7.4 by Substituted Sulfonatocalix[4]arenes

Schneider

Bierwisch²,

Koller³

et al. 2016

Angew Chem Int Ed

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Sulfonatocalix [4]arenes with an appended hydroxamic acid residue can detoxify VX and related V-type neurotoxico rganophosphonates with half-lives down to 3min in aqueous buffer at 37 8 8Cand pH 7.4. The detoxification activity is attributed to the millimolar affinity of the calixarene moiety for the positively charged organophosphonates in combination with the correct arrangement of the hydroxamic acid group. The reaction involves phosphonylation of the hydroxamic acid followed by aLossen rearrangement, thus rendering the mode of action stoichiometric rather than catalytic. Nevertheless, these calixarenes are currently the most efficient low-molecular-weight compounds for detoxifying persistent V-type nerve agents under mild conditions.T hey thus represent lead structures for novel antidotes that allow treatment of poisonings by these highly toxic chemicals.With ap ercutaneous LD 50 value of 10 mg/human, the organophosphonate (OP) O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX;F igure 1) is one of the most toxic and most persistent chemical warfare agents. [1] Analogues that likewise have the amino group in the side chain and the relatively stable phosphono-thioester bond are similarly harmful.Thetoxicity of nerve agents is mainly related to their high propensity to covalently modify aserine residue in the active site of the enzyme acetylcholinesterase (AChE).[2] In this form, AChE is unable to perform its function, namely to degrade the neurotransmitter acetylcholine,w hose accumulation leads to severe toxic effects on the central and peripheral nervous system and ultimately to death.Ap romising concept to treat poisonings by nerve agents involves the use of proteins,s oc alled bioscavengers,t hat detoxify OPs before clinical signs occur.[3] Bioscavengers have drawbacks,h owever, for example,l ow in vivo stability and immunogenicity,t hus rendering synthetic scavengers attractive alternatives.[4] With only af ew exceptions, [5] studies on synthetic scavengers have so far concentrated on cyclodextrin derivatives.[6] Their mode of action is expected to resemble that of proteins,w ith an initial complexation step that positions the phosphorus atom of the nerve agent close to asubstituent on the cyclodextrin ring to facilitate the reaction. Despite notable success in this context, [6] cyclodextrins that detoxify V-type nerve agents have so far remained elusive.A possible explanation could be that V-type nerve agents are poor substrates for cyclodextrins because of their protonated side chain amino groups and, hence,p olar nature at physiological pH values. [7] If this assumption is correct, hosts for ammonium ions in water should be more promising scaffolds for scavengers for V-type nerve agents.This idea is consistent with established design principles of supramolecular catalysts and reagents. [8] Ajami and Rebek proposed the use of resorcinarenederived cavitands as OP scavengers.[5c] They described the synthesis of functionalized derivatives that could be used as ab asis for such scav...

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“…[16] Other synthetic receptors have also been developed for selective binding to posttranslational modifications, including methylated lysine and arginine residues. [17,18] These synthetic receptors are advantageous over covalent tags, as they do not alter the protein or peptide structure, and therefore allow for noncovalent capture and subsequent competition-mediated release of native protein structures for further study.…”

Section: Supramolecular Protein Immobilization and Detectionmentioning

confidence: 99%

Supramolecular strategies for protein immobilization and modification

Finbloom

Francis

2018

Current Opinion in Chemical Biology

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Protein immobilization and modification are widely used techniques in the fields of chemical biology and biomaterials science. While covalent strategies based on small molecules are traditionally used, supramolecular chemistry offers numerous useful opportunities for guiding the modification locations on complex protein landscapes and introducing different degrees of reversibility into the products. In this opinion, we highlight recent advances in using supramolecular interactions, particularly host-guest chemistry, for controlling protein modification and immobilization. We discuss supramolecular strategies for protein-conjugate purification and capture, as well as for protein modification via host-guest interactions and metal coordination. Lastly, we address recent advances in utilizing supramolecular interactions to direct covalent protein modification. These examples of supramolecular chemical biology present opportunities to advance a wide range of applications, including proteomics and drug delivery.

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Host–guest chemistry that directly targets lysine methylation: synthetic host molecules as alternatives to bio-reagents

Cited by 51 publications

References 86 publications

Site-Selective Sensing of Histone Methylation Enzyme Activity via an Arrayed Supramolecular Tandem Assay

Site-Selective Sensing of Histone Methylation Enzyme Activity via an Arrayed Supramolecular Tandem Assay

Detoxification of VX and Other V‐Type Nerve Agents in Water at 37 °C and pH 7.4 by Substituted Sulfonatocalix[4]arenes

Supramolecular strategies for protein immobilization and modification

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