A Small-Molecule Guanidinium Receptor: The Arginine Cork

Bell, Thomas W.; Khasanov, Alisher; Drew, Michael G. B.; Filikov, Anton V.; James, Thomas Leroy

doi:10.1002/(sici)1521-3773(19990903)38:17<2543::aid-anie2543>3.0.co;2-9

Cited by 52 publications

(38 citation statements)

References 19 publications

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“…BD and CD did not affect DA transport velocities at concentrations below 10 mM (data not shown). Arg Cork was used at a concentration of 200 M, ϳ4-fold higher than the K d of Arg Cork for Arg in dipeptides (Bell et al, 1999).…”

Section: Cocaine Attenuation Of Arg Modifying Agents In Rat Striatummentioning

confidence: 99%

“…The work reported here describes the effects of arginine (Arg)-selective chemical modification of the DAT using a selection of covalently modifying agents (phenylglyoxal (PG), 2,3-butanedione (BD), and 1,2-cyclohexanedione (CD)), as well as the noncovalent modifier of Arg, tetrahydro [1,10]phenanthrolino [2,3b] [1,10]phenanthroline-2,13-dicarboxylic acid, known as the Arg Cork (Bell et al, 1999(Bell et al, , 2002.…”

Section: Introductionmentioning

confidence: 99%

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Covalent and noncovalent chemical modifications of arginine residues decrease dopamine transporter activity

Volz

Kim

Schenk

2004

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Rotating disk electrode voltammetry was used to measure dopamine (DA) transport in rat striatum and in human embryonic kidney cells expressing the rat dopamine transporter (DAT). The goals of this study were to determine 1) if arginine (Arg) selective agents could alter DA transport, and 2) if DA analogs and DAT inhibitors could attenuate the effects of these agents on the DAT. Phenylglyoxal (PG), Hill coefficient 2.5, and other Arg selective agents decreased DA transport velocities. DA, Hill coefficient 1.0, and its analogs 3-hydroxyphenethylamine and 4-hydroxyphenethylamine attenuated the effects of PG on the DAT while phenethylamine did not. The tropane-based DAT inhibitors cocaine, WIN 35065-2, and WIN 35428 also attenuated the effects of PG. Benztropine, GBR 12935, and GBR 12909 did not. Thus, Arg residues are important for DAT activity and the results suggest that DA and cocaine both interact with Arg residues. Structure-activity studies suggest that DA interacts with Arg through its catechol hydroxyl groups and cocaine through the ester linkage attached to carbon 2 of the tropane ring. The results that 1). DA and cocaine may interact with the same functionally important Arg residue at the DAT, and 2). some members of the tropane and 1,4-dialkylpiperazine classes of DAT inhibitors may interact differently with DAT-derived Arg residue(s) furthers the notion that DAT activity sparing antagonists of cocaine can be designed.

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Section: Cocaine Attenuation Of Arg Modifying Agents In Rat Striatummentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Covalent and noncovalent chemical modifications of arginine residues decrease dopamine transporter activity

Volz

Kim

Schenk

2004

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“…9–11 If a synthetic host molecule can be designed which exploits aromatic interactions for the specific recognition of single amino acid residues in peptides and proteins, it may be able to interfere in a predictable way with protein folding, aggregation or enzyme catalysis. Although a plethora of artificial receptor molecules have been developed for amino acids (e.g., crown ethers, 12–14 calixarenes, 15–19 cyclophanes, 20 polyaza-arenes, 21 galactose derivatives, 22 molecular tweezers with substituted phosphonate groups, 23 peptide units, 24 or porphyrine rings 25 as side walls), most of them provide little selectivity for a single residue. In this respect the molecular benzene tweezers 1 are remarkable, since they reject all other amino acids and only bind to lysine and arginine.…”

Section: Introductionmentioning

confidence: 99%

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

2016

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Molecular tweezers represent the first class of artificial receptor molecules that made the way from a supramolecular host to a drug candidate with promising results in animal tests. Due to their unique structure, only lysine and arginine are well complexed with exquisite selectivity by a threading mechanism, which unites electrostatic, hydrophobic and dispersive attraction. However, tweezer design must avoid self-dimerization, self-inclusion and external guest binding. Moderate affinities of the molecular tweezers towards sterically well accessible basic amino acids with fast on and off rates protect normal proteins from a potential interference with their biological function. However, the early stages of abnormal Aβ, α-synuclein, and TTR assembly are redirected upon tweezer binding towards the generation of amorphous non-toxic material that can be degraded by the intracellular and extracellular clearance mechanisms. Thus, specific host–guest chemistry between aggregation-prone proteins and lysine/arginine binders rescues cell viability and restores animal health in models of AD, PD, and TTR amyloidosis.

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“…Recognition of arginine can also be accomplished through the formation of salt bridges. A variety of solution phase reagents such as the arginine cork [7] which incorporates two carboxylates or Schrader and coworker's molecular tweezers [8] which contain two phosphates are based on the salt bridge approach. In the gas phase, Zenobi and co-workers have utilized disulfonic acids for the recognition of arginine in matrix assisted laser desorption ionization (MALDI) experiments [9].…”

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confidence: 99%

Selective molecular recognition of arginine by anionic salt bridge formation with bis-phosphate crown ethers: implications for gas phase peptide acidity from adduct dissociation

Julian

Beauchamp

2004

J. Am. Soc. Mass Spectrom.

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Arginine forms a stable noncovalent anionic salt bridge complex with DP (a crown ether which contains two endocyclic dialkylhydrogenphosphate esters). Abundant adduct formation with DP is observed for complexes with arginine, YAKR, HPPGFSPFR, AAKRKAA, RR, RPPGF-SPFR, RYLGYL, RGDS, and YGGFMRGL in electrospray ionization mass spectrometry (ESI-MS) experiments. DFT calculations predict a hydrogen bonded salt bridge structure with a protonated guanidinium flanked by two deprotonated phosphates to be the lowest energy structure. Dissociation of DP/peptide adducts reveals that, in general, the relative gas phase acidity of a peptide is dependent on peptide length, with longer peptides being more acidic. In particular, peptides that are six residues or more in length can stabilize the deprotonated C-terminus by extensive hydrogen bonding with the peptide backbone. Dissociation of DP/peptide complexes often yields the deprotonated peptide, allowing for the facile formation of anionic peptides that otherwise would be difficult to generate in high abundance. Although DP has a preference for binding to arginine residues in peptides, DP is also observed to form less abundant complexes with peptides containing multiple lysines. Lys-Xxx-Lys and Lys-Lys sequences form low abundance anionic adducts with DP. For example, KKKK exclusively forms a double adduct with one net negative charge on the complex. T he development of methods that enable the rapid identification and characterization of proteins, especially those providing information relating to sequence, structure, and function, will facilitate new discoveries in the emerging field of proteomics [1,2,3]. Toward this goal, we have undertaken the development and systematic study of reagents that will selectively bind to peptides and proteins though specific noncovalent complexation of targeted amino acids both in solution and in the gas phase. For example, electrospray ionization (ESI) experiments employing 18-crown-6 ether (18C6) to form noncovalent complexes with lysine containing peptides and proteins have yielded valuable information about sequence and structure [4]. In these experiments, attachment of 18C6 to peptides yields quantitative information about the number of lysines present, whereas complexation with proteins reveals information about the tertiary structure and surface availability of lysine residues [4]. In a related work, 18C6 serves as a molecular scaffold for the attachment of a diazo functional group, yielding a reagent known as a "molecular mousetrap" because of its ability to convert noncovalent complexes into covalently bound molecules following appropriate activation to form a reactive carbene [5].Similar recognition of the side chain of arginine has been accomplished with larger crown ethers such as dibenzo-30-crown-10, which forms extensive hydrogen bonds with the protonated alkyl-guanidinium side chain of arginine [6]. Recognition of arginine can also be accomplished through the formation of salt bridges. A variety of solution phase reagents such...

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A Small-Molecule Guanidinium Receptor: The Arginine Cork

Cited by 52 publications

References 19 publications

Covalent and noncovalent chemical modifications of arginine residues decrease dopamine transporter activity

Covalent and noncovalent chemical modifications of arginine residues decrease dopamine transporter activity

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

Selective molecular recognition of arginine by anionic salt bridge formation with bis-phosphate crown ethers: implications for gas phase peptide acidity from adduct dissociation

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