Bifunctional fusion proteins containing the sequence of the bradykinin homologue maximakinin: activities at the rat bradykinin B<sub>2</sub> receptor

Charest‐Morin, Xavier; Lodge, Robert; Marceau, François

doi:10.1139/cjpp-2017-0692

Cited by 2 publications

(11 citation statements)

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“…A spacer sequence has been systematically used in the reported designs. For B 2 Rs, an amphibian peptide possessing the intact BK sequence at its Cterminus and a 10-residue hydrophilic extension, MK -agonist [76,77] (see section 2). The compact enhanced green fluorescent protein (EGFP) was successfully fused to MK to produce a nanomolar potency fluorescent B 2 R probe [76,77] (Fig.…”

Section: Biotechnological Ligandsmentioning

confidence: 99%

“…The detection of B 1 R expression has a diagnostic interest. The cardiovascular and renal benefits of B 2 R stimulation are already obtained in patients via ACE inhibition, but we have argued that a more direct approach based on biotechnological or prodrug agonists could be tried [73][74][75]77].…”

Section: Perspectivesmentioning

confidence: 99%

“…Maximakinin (MK), an amphibian sequence that contains BK at its C-terminus and a 10-residue N-terminal extension, is an agonist with a fair potency at the rabbit and rat B 2 Rs [32] and the extension should protrude out in the extracellular fluid. EGFP-MK is a fluorescent fusion protein based on MK that is a nanomolar agonist of the rabbit and rat B 2 R and is translocated to endosomes with it [33,76,77]. APEX2-(Asn-Gly) 15 -MK is an enzymatic ligand, endowed with peroxidase activity [77].…”

Section: Perspectivesmentioning

confidence: 99%

“…EGFP-MK is a fluorescent fusion protein based on MK that is a nanomolar agonist of the rabbit and rat B 2 R and is translocated to endosomes with it [33,76,77]. APEX2-(Asn-Gly) 15 -MK is an enzymatic ligand, endowed with peroxidase activity [77]. Right: the optimal agonist of the human B 1 R is Lys-des-Arg 9 -BK and its N-terminus is also closed to the receptor-extracellular fluid interface [2].…”

Section: Perspectivesmentioning

confidence: 99%

“…* construction inherently resistant to extracellular and cytosolic peptidases/proteases; bifunctional construction. Reproduced in part, in a modified manner, from Charest-Morin et al [77] with the permission of the Editor. endocytosis [102], that is largely inhibited by receptor truncation [56,82,103] another less defined Rab4-facilitated mechanism has also been identified [97].…”

Section: Perspectivesmentioning

confidence: 99%

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Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

et al. 2018

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Kinins are the small and fragile hydrophilic peptides related to bradykinin (BK) and derived from circulating kininogens via the action of kallikreins. Kinins bind to the preformed and widely distributed B receptor (BR) and to the inducible B receptor (BR). BRs and BRs are related G protein coupled receptors that possess natural agonist ligands of nanomolar affinity (BK and Lys BK for BRs, Lys-des-Arg-BK for BR). Decades of structure-activity exploration have resulted in the production of peptide analogs that are antagonists, one of which is clinically used (the BR antagonist icatibant), and also non-peptide ligands for both receptor subtypes. The modification of kinin receptor ligands has made them resistant to extracellular or endosomal peptidases and/or produced bifunctional ligands, defined as agonist or antagonist peptide ligands conjugated with a chemical fluorophore (emitting in the whole spectrum, from the infrared to the ultraviolet), a drug-like moiety, an epitope, an isotope chelator/carrier, a cleavable sequence (thus forming a pro-drug) and even a fused protein. Dual molecular targets for specific modified peptides may be a source of side effects or of medically exploitable benefits. Biotechnological protein ligands for either receptor subtype have been produced: they are enhanced green fluorescent protein or the engineered peroxidase APEX2 fused to an agonist kinin sequence at their C-terminal terminus. Antibodies endowed with pharmacological actions (agonist, antagonist) at BR have been reported, though not monoclonal antibodies. These findings define classes of alternative ligands of the kinin receptor of potential therapeutic and diagnostic value.

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Section: Biotechnological Ligandsmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

et al. 2018

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Bradykinin receptors: Agonists, antagonists, expression, signaling, and adaptation to sustained stimulation

Marceau

Bachelard

Bouthillier

et al. 2020

International Immunopharmacology

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The Journal of Angioedemasit amet INTRODUCTION The pharmacology of bradykinin (BK)-related peptides, the kinins, has come a long way in recent decades, with the pharmacologic and then the molecular definition of 2 G protein-coupled receptors (GPCRs) that mediate their cellular actions, the B 1 and B 2 receptors (B 1 R, B 2 R). 1 Additional modern research tools include mouse strains in which one or both of the genes coding for kinin receptors have been deleted ("gene knockout" models). 2 The formation of kinins and their degradation by interesting peptidases, such as angiotensin-converting enzyme, will not be covered in the present text. The arduous nature of the analytic biochemistry of BK-related peptides is outlined elsewhere. 3 We rather propose an excursion into the pharmacology of kinins, the first author having been a spectator and an actor in the field for the past 35 years. There will be a strong autobiographic bias in the selection of the illustration material. We hope this partiality will be forgiven in light of the generous invitation he has received to summarize the field during an oral presentation at the 8th C1-Inhibitor Deficiency Workshop. BRADYKININ RECEPTOR LIGANDS: AGONISTS AND ANTAGONISTS The receptors for bradykinin were initially defined in the late 1970s and 1980s using pharmacologic criteria. The B 1 R was historically the first defined using both a typical potency order of agonists and a class of specific antagonists. This somewhat atypical receptor subtype is optimally responsive to fragments of the native kinins (BK and Lys-BK) in which the Arg 9 residue has been removed (des-Arg 9-BK, Lys-des-Arg 9-BK, respectively; Fig. 1). 4 The early peptide antagonists were simply des-Arg 9 sequences in which Phe 8 was replaced with a residue possessing an aliphatic side chain, such as Leu. In retrospect, it is now clear that the native kinins produced by the kallikreins, either BK or Lys-BK (kallidin), are selective agonists of the physiologically prominent B 2 R subtype that has been consolidated with specific peptide antagonists in the 1980s by Professor John M. Stewart and colleagues. The B 2 R antagonists typically possess a constrained peptide backbone due to the inclusion of bulky nonnatural amino acids that also confer resistance ABSTRACT Bradykinin-related peptides, the kinins, are blood-derived peptides that stimulate 2 G protein-coupled receptors, the B 1 and B 2 receptors (B 1 R, B 2 R). The pharmacologic and molecular identities of these 2 receptor subtypes will be succinctly reviewed, with emphasis on drug development, receptor expression, signaling, and adaptation to persistent stimulation. Peptide and nonpeptide antagonists and fluorescent ligands have been produced for each receptor. The B 2 R is widely and constitutively expressed in mammalian tissues, whereas the B 1 R is mostly inducible under the effect of cytokines during infection and immunopathology. Both receptor subtypes mediate the vascular aspects of inflammation (vasodilation, edema formation). On this basis, icatibant...

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Bifunctional fusion proteins containing the sequence of the bradykinin homologue maximakinin: activities at the rat bradykinin B₂ receptor

Cited by 2 publications

References 33 publications

Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

Bradykinin receptors: Agonists, antagonists, expression, signaling, and adaptation to sustained stimulation

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Bifunctional fusion proteins containing the sequence of the bradykinin homologue maximakinin: activities at the rat bradykinin B2 receptor

Cited by 2 publications

References 33 publications

Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

Bradykinin receptors: Agonists, antagonists, expression, signaling, and adaptation to sustained stimulation

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Bifunctional fusion proteins containing the sequence of the bradykinin homologue maximakinin: activities at the rat bradykinin B₂ receptor