Discovery of new C3aR ligands. Part 1: Arginine derivatives

Denonne, Frédéric; Binet, Sophie; Burton, Maggi; Collart, Philippe; Dipesa, Alan; Ganguly, Tanmoy; Giannaras, Alexander; Kumar, Seema; Lewis, Timothy A.; Maounis, F.; Nicolas, Jean‐Marie; Mansley, Tamsin E.; Pasau, Patrick; Preda, Dorin V.; Stebbins, Karin; Volosov, Alexander; Zou, Da

doi:10.1016/j.bmcl.2007.04.022

Cited by 15 publications

(20 citation statements)

References 13 publications

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“…An aminopiperidine antagonist developed by the same group (Fig. 4D), which lacks the Arg but has poorer antagonist activity (pIC 50 = 5.8) and derivatization, has so far resulted only in higher affinity compounds with agonist activity (Denonne et al, 2007b).…”

Section: Structure Of Complement Peptidesmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

Klos

Wende²,

Wareham³

et al. 2013

Pharmacol Rev

227

245

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Section: Structure Of Complement Peptidesmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

Klos

Wende²,

Wareham³

et al. 2013

Pharmacol Rev

227

245

View full text Add to dashboard Cite

“…Synthetic agonists that act through C3aR, but do not degrade as C3a does, can be expected to have immunostimulating and degranulating activities, whereas stable antagonists may be valuable new anti-inflammatory therapeutics. However, despite decades of effort by academia and the pharmaceutical industry, no small organic molecules have yet been reported as potent and selective C3aR agonists or antagonists [28][29][30][31][32] .…”

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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“…In the same year, another study (Denonne et al, 2007b) reported a new compound (pIC 50 7.5 vs 20 pM [ 125 I]-C3a) with higher affinity for C3aR than SB290157. This new compound was a constrained analogue of SB290157 with a rigid furan ring and an arginine residue (Figure 4.2 D).…”

Section: Chapter 4 Towards C3a Receptor Antagonists 161mentioning

confidence: 99%

“…Furthermore, the cleavage of C3a at the arginine position by carboxypeptidases N leads to the complete loss of biological activity because C3a-des Arg does not bind to C3aR (Wetsel et al, 2000). The modification of the arginine residue by replacing with arginine mimetics may improve bioavailability, solubility and, metabolic stability of the compounds (Denonne et al, 2007b) and might be part of future studies.…”

Section: Structural Modification Of C3ar Antagonist: Sb290157mentioning

confidence: 99%

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Molecular pharmacology of C3aR modulators

Singh¹

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The complement system plays key roles in both the innate (non-specific) and acquired (specific) immune response. Complement activation is a tightly regulated process, which takes place in a sequential manner by at least three pathways. All of these pathways generate a small anaphylatoxin protein called C3a. C3a signals immune cells which infiltrate to sites of infection or injury and mount inflammatory responses leading to elimination of pathogens or damaged cells and induction of adaptive immunity. Genetic deficiency of C3 results in susceptibility to bacterial infection. However, in excess C3a can be harmful and catalyses the pathogenesis of many disease conditions. To date, there have been no truly selective and potent C3a receptor agonists/antagonists. Therefore, the purpose of this thesis was to explore the potential to develop a small molecule C3aR agonist/antagonist that can be a useful as a pharmacological probe or biomarker for studying the physiological and pharmacological roles of C3a. Chapter 1 briefly describes basic pharmacology terminology and reviews current knowledge of GPCRs, GPCR intracellular signalling pathways,

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Discovery of new C3aR ligands. Part 1: Arginine derivatives

Cited by 15 publications

References 13 publications

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

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

Molecular pharmacology of C3aR modulators

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