Over One Hundred Peptide‐Activated G Protein‐Coupled Receptors Recognize Ligands with Turn Structure

Tyndall, Joel D. A.; Pfeiffer, Bernhard; Abbenante, Giovanni; Fairlie, David P.

doi:10.1002/chin.200521282

Cited by 17 publications

(20 citation statements)

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“…Indeed, induced fit requirements can dictate shapes that are quite distinct from crystal conformations (27). In light of this fact, it is possible that there is no β-turn in the active conformation of enkephalins or that a β-turn between amides 2 and 4 might have been selected by DOPR (28).…”

Section: Introductionmentioning

confidence: 99%

Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor

Proteau-Gagné

Bournival²,

Rochon³

et al. 2010

ACS Chem. Neurosci.

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The role of each of the four amide bonds in Leu 5 -enkephalin was investigated by systematically and sequentially replacing each with its corresponding trans-alkene. Six Leu 5 -enkephalin analogs based on six dipeptide surrogates and two Met 5 -enkephalin analogs were synthesized and thoroughly tested using a δ-opioid receptor internalization assay, an ERK1/2 activation assay, and a competition binding assay to evaluate their biological properties. We observed that an E-alkene can efficiently replace the first amide bond of Leu 5 -and Met 5 -enkephalin without significantly affecting biological activity. By contrast, the second amide bond was found to be highly sensitive to the same modification, suggesting that it is involved in biologically essential intra-or intermolecular interactions. Finally, we observed that the affinity and activity of analogs containing an E-alkene at either the third or fourth position were partially reduced, indicating that these amide bonds are less important for these intra-or intermolecular interactions. Overall, our study demonstrates that the systematic and sequential replacement of amide bonds by E-alkene represents an efficient way to explore peptide backbones.

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Section: Introductionmentioning

confidence: 99%

Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor

Proteau-Gagné

Bournival²,

Rochon³

et al. 2010

ACS Chem. Neurosci.

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“…However, the use of proteins in science, industry and medicine is still significantly restricted by their high cost of manufacture, chemical instability, immunogenicity and poor bioavailability. The need to overcome these deficiencies has driven many chemical efforts, but it has been extremely challenging to reproduce the exquisitely potent and specific actions of proteins [1][2][3][4][5][6] . The biological functions of some proteins are localized in very short polypeptide segments stabilized in specific structures (two to four helical turns, isolated b-turns, strands/sheets, and their combinations) by their protein environments 7,8 .…”

mentioning

confidence: 99%

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

et al. 2013

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A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turninducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weight o500 Da) examined for receptor affinity and cellular responses have the same high potencies, functional profile and specificity of action as C3a protein, but greater plasma stability and bioavailability.

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“…Unusual amino acid building blocks are often incorporated to elucidate pharmacophore interactions with the receptor [67,91]. Determination of the pharmacophore presents an opportunity for downsizing the peptide to the essential core structure or in some cases even to a novel class of small molecules [54,75,[92][93][94][95][96].…”

Section: Role Of Medicinal Chemistry In Development Of Peptide-based mentioning

confidence: 99%

Cone Snail Venomics: From Novel Biology to Novel Therapeutics

et al. 2014

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Peptide neurotoxins from cone snails called conotoxins are renowned for their therapeutic potential to treat pain and several neurodegenerative diseases. Inefficient assay-guided discovery methods have been replaced by high-throughput bioassays integrated with advanced MS and next-generation sequencing, ushering in the era of 'venomics'. In this review, we focus on the impact of venomics on the understanding of cone snail biology as well as the application of venomics to accelerate the discovery of new conotoxins. We also discuss the continued importance of medicinal chemistry approaches to optimize conotoxins for clinical use, with a descriptive case study of MrIA featured.

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Over One Hundred Peptide‐Activated G Protein‐Coupled Receptors Recognize Ligands with Turn Structure

Cited by 17 publications

References 1 publication

Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor

Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

Cone Snail Venomics: From Novel Biology to Novel Therapeutics

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