Oligoproline helices as structurally defined scaffolds for oligomeric G protein-coupled receptor ligands

Bonger, Kimberly M.; Kapoerchan, Varsha V.; Grotenbreg, Gijsbert M.; Koppen, Chris J. van; Timmers, Cornelis M.; Marel, Gijsbert A. van der; Overkleeft, Herman S.

doi:10.1039/b923556f

Cited by 25 publications

(21 citation statements)

References 29 publications

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“…Oligoprolines, which are amongst the most rigid peptides, have become increasingly popular in recent years as “molecular rulers” and “molecular scaffolds” 1. They have been used for energy transfer,2–8 distance measurements in biomolecules,9, 10 tumor targeting,11, 12 electron‐transfer studies,13, 14 the development of protein– protein interaction inhibitors,15 hierarchical supramolecular assemblies,16 and for the size‐controlled formation of metal nanoparticles 17. Thus, detailed knowledge of the dimensions and conformational rigidity of oligoprolines is highly sought after.…”

Section: Introductionmentioning

confidence: 99%

Shape Persistence of Polyproline II Helical Oligoprolines

Garbuio

Lewandowski

Wilhelm

et al. 2015

Chemistry A European J

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Oligoprolines are commonly used as molecular scaffolds. Past studies on the persistence length of their secondary structure, the polyproline II (PPII) helix, and on the fraction of backbone cis amide bonds have provided conflicting results. We resolved this debate by studying a series of spin-labeled proline octadecamers with EPR spectroscopy. Distance distributions between an N-terminal Gd(III) -DOTA (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) label and a nitroxide label at one of five evenly spaced backbone sites allowed us to discriminate between the flexibility of the PPII helix and the cis amide contributions. An upper limit of 2 % cis amide bonds per residue was found in a 7:3 (v/v) water/glycerol mixture, whereas cis amides were not observed in trifluoroethanol. Extrapolation of Monte Carlo models from the glass transition to ambient temperature predicts a persistence length of ≈3-3.5 nm in both solvents. The method is generally applicable to any type of oligomer for which the persistence length is of interest.

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Section: Introductionmentioning

confidence: 99%

Shape Persistence of Polyproline II Helical Oligoprolines

Garbuio

Lewandowski

Wilhelm

et al. 2015

Chemistry A European J

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“…17o, p, 32c, 59 In general, the azidoacetate reacted more rapidly than the azidoproline, likely due to reduced steric restriction, though both were effective in azide-alkyne coupling reactions.…”

Section: Resultsmentioning

confidence: 99%

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

et al. 2013

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Functionalized proline residues have diverse applications. Herein we describe a practical approach, proline editing, for the synthesis of peptides with stereospecifically modified proline residues. Peptides are synthesized by standard solid-phase-peptide-synthesis to incorporate Fmoc-Hydroxyproline (4R-Hyp). In an automated manner, the Hyp hydroxyl is protected and the remainder of the peptide synthesized. After peptide synthesis, the Hyp protecting group is orthogonally removed and Hyp selectively modified to generate substituted proline amino acids, with the peptide main chain functioning to “protect” the proline amino and carboxyl groups. In a model tetrapeptide (Ac-TYPN-NH2), 4R-Hyp was stereospecifically converted to 122 different 4-substituted prolyl amino acids, with 4R or 4S stereochemistry, via Mitsunobu, oxidation, reduction, acylation, and substitution reactions. 4-Substituted prolines synthesized via proline editing include incorporated structured amino acid mimetics (Cys, Asp/Glu, Phe, Lys, Arg, pSer/pThr), recognition motifs (biotin, RGD), electron-withdrawing groups to induce stereoelectronic effects (fluoro, nitrobenzoate), handles for heteronuclear NMR (19F:fluoro; pentafluorophenyl or perfluoro-tert-butyl ether; 4,4-difluoro; 77SePh) and other spectroscopies (fluorescence, IR: cyanophenyl ether), leaving groups (sulfonate, halide, NHS, bromoacetate), and other reactive handles (amine, thiol, thioester, ketone, hydroxylamine, maleimide, acrylate, azide, alkene, alkyne, aryl halide, tetrazine, 1,2-aminothiol). Proline editing provides access to these proline derivatives with no solution phase synthesis. All peptides were analyzed by NMR to identify stereoelectronic and steric effects on conformation. Proline derivatives were synthesized to permit bioorthogonal conjugation reactions, including azide-alkyne, tetrazinetrans-cyclooctene, oxime, reductive amination, native chemical ligation, Suzuki, Sonogashira, cross-metathesis, and Diels-Alder reactions. These proline derivatives allowed three parallel bioorthogonal reactions to be conducted in one solution.

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“…It was suggested that a spacer length of 20–24 atoms was ideal when directed in a specific orientation to allow for binding of the two pharmacophores at the respective receptors 35. The variety of spacer groups are presented in Table 2, accompanied by additional examples including some of the vast array of spacers synthesised by Bonger et al 69–71. who generated bivalent ligands targeting the gonadotropin releasing hormone receptor (GnRHR) with rigid benzene‐based scaffolds ( 21 , 23 , 26 ) 70…”

Section: General Features Of Bivalent Ligandsmentioning

confidence: 99%

“…It is interesting to note the use of polybutylene glycol spacer groups,73 which have been designed to counter the natural coil‐like conformation obtained when using PEG spacers,74–76 whilst retaining an element of hydrophilicity and flexibility. On the other hand, multiple oligoproline residues ( 24 ) have been used to form well‐defined helical structures77 for the synthesis of specifically oriented bivalent ligands with a coiled spacer 69. Another alternative to improving the hydrophilicity of the bivalent ligand (Table 2) is the incorporation of piperazine into the spacer group ( 28 ), which has slightly less flexibility than an alkyl chain and PEG spacer, but slightly more than polyamide chains, and for this reason it is an important design consideration for bivalent ligands.…”

Section: General Features Of Bivalent Ligandsmentioning

confidence: 99%

Design Strategies for Bivalent Ligands Targeting GPCRs

Shonberg¹,

Scammells²,

Capuano³

2011

ChemMedChem

127

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Specifically designed bivalent ligands targeting G protein-coupled receptor (GPCR) dimeric structures have become increasingly popular in recent literature. The advantages of the bivalent approach are numerous, including enhanced potency and receptor subtype specificity. However, the use of bivalent ligands as potential pharmacotherapeutics is limited by problematic molecular properties, such as high molecular weight and lipophilicity. This minireview focuses on the design of bivalent ligands recently described in the literature; discussing the choice of lead pharmacophore, the position and nature of the attachment point for linking the two pharmacophore units, and the length and composition of the spacer group. Furthermore, this minireview distils the molecular descriptors of the bivalent ligands that exhibit in vivo activity, as well as highlights their ability to access the central nervous system.

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Oligoproline helices as structurally defined scaffolds for oligomeric G protein-coupled receptor ligands

Cited by 25 publications

References 29 publications

Shape Persistence of Polyproline II Helical Oligoprolines

Shape Persistence of Polyproline II Helical Oligoprolines

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

Design Strategies for Bivalent Ligands Targeting GPCRs

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