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

Abstract

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.

Kinins and Cytokines in COVID-19: A Comprehensive Pathophysiological Approach

“…Kallikreins are serine proteases and can be divided in plasma kallikrein and tissue kallikreins ( Figure 1). The plasma and tissue kallikreins release the vasoactive peptides known as kinins (all sorts of BKs) that cause relaxation of vascular smooth muscle and increased vascular permeability 4,9 . Plasma kallikrein processes highmolecular-weight kininogen (HMWK produced by the liver 8 ) into bradykinin, while tissue kallikrein processes low-molecular-weight kininogen (LMWK produced by the liver 8 ) and results in Lys-BK ( Figure 1).…”

“…However, for ACE inhibitors and ARBs it is a much more complicated story. Since most of the attention was focused on the RAS system and its interaction with modulating the vascular system and inflammation, the other major role of ACE and ACE2 for the regulation of the kinin-kallikrein system was lacking attention 4,5 .…”

Immunological aspects of COVID-19: What do we know?

“…It is assumed that the enzymatic activity of the ACE-2 receptor inactivates des-Arg9 bradykinin, which is a ligand for B1. Furthermore, unlike B2, B1 is regulated by pro-inflammatory cytokines[ 59 ]. Interestingly, without the inactivation of B1 ligands, increased local vascular permeability is observed in lung mucosa, leading to angioedema.…”

A Systematic Review of Molecular Imaging Agents Targeting Bradykinin B1 and B2 Receptors

“…Since then, many kinin derivatives have been synthesized and investigated. These sequences include modifications (e.g., amino acid substitutions, reduction of amide bonds, N -terminal capping [ 24 ]) that are aimed at conferring selectivity, stability to peptidases, agonist/antagonist properties and prolonging in vivo pharmacological effects [ 25 ]. Moreover, the plasticity of kinins also enables their use as targeting vectors to carry fluorophores, drugs, and radioactivity ( Figure 2 ).…”

“…Arrows indicate positions of potential cleavage. AmM: aminopeptidase M; AmP: aminopeptidase P; NEP 24.11: neutral endopeptidase 24.11; ACE: angiotensin-converting enzyme; CPM: carboxypeptidase M. Figure adapted from Marceau, F., et al [ 25 ].…”