Function and structure of bradykinin receptor 2 for drug discovery

Abstract

Type 2 bradykinin receptor (B2R) is an essential G protein-coupled receptor (GPCR) that regulates the cardiovascular system as a vasodepressor. Dysfunction of B2R is also closely related to cancers and hereditary angioedema (HAE). Although several B2R agonists and antagonists have been developed, icatibant is the only B2R antagonist clinically used for treating HAE. The recently determined structures of B2R have provided molecular insights into the functions and regulation of B2R, which shed light on structure-based drug design for the treatment of B2R-related diseases. In this review, we summarize the structure and function of B2R in relation to drug discovery and discuss future research directions to elucidate the remaining unknown functions of B2R dimerization.

Unraveling the crosstalk between renin‐angiotensin system receptors

“…26 These heteromers exhibit negative crosstalk in cAMP and MAPK signaling pathways in microglia. Bradykinin, acting through the type 2 receptor (B 2 R), elicits vasoprotective actions 30 opposing Ang II responses. AT 1 R and B 2 R directly communicate with each other, forming stable heteromers that enhance Ang II-stimulated G q/11 and G i activation, and induce alterations in receptor sequestration.…”

Plasma Kinins- A Pharmacological Perspective

“…The experimentations using snake venom since the identification of captopril decades back are still in the continuum [90]. Receptor modeling and molecular docking studies for understanding the various pharmacological roles of bradykinin receptors are on the rise [91]. Bradykinin is also considered an important component in the pathophysiology of chronic pain and itch [92].…”

DNA-templated self-assembly of bradykinin into bioactive nanofibrils

“…7,8 According to studies conducted during the COVID-19 pandemic, the downregulation of the expression of the angiotensin-converting enzyme 2 (ACE2) inhibits degradation of both BK and its analog des-Arg 9 -BK, promoting a ''bradykinin storm'' that increases vascular permeability and exacerbates the severity of disease symptoms. 9,10 Although the pharmacological mechanisms of BK and its analogs are relatively well understood for decades, 1,2 their use in the development of nanostructured materials is not widely reported in the literature. While a few recent reports demonstrate hybrid systems involving the conjugation of BK with polymeric chains 11 and the folding of 2D nanoparticles on solid substrates, 12 studies demonstrating BK-based nanostructured assemblies are still lacking.…”

“…Bradykinin (BK) is a potent bioactive peptide, belonging to the kinin protein group, and exhibiting strong agonistic activity for the B2 receptor of GPCR proteins. 1,2 Its discovery more than 70 years ago 3 marked a milestone in medical research, as scientists soon realized its ability to modulate intracellular calcium levels, control blood pressure, produce a vasodilator effect, and play a significant role as a pro-inflammatory mediator. 4–6 This remarkable peptide hormone continues to surprise the research community, and recently, it has been proposed to play a pivotal role in the pathophysiology of SARS-CoV-2.…”

“…Although the pharmacological mechanisms of BK and its analogs are relatively well understood for decades, 1,2 their use in the development of nanostructured materials is not widely reported in the literature. While a few recent reports demonstrate hybrid systems involving the conjugation of BK with polymeric chains 11 and the folding of 2D nanoparticles on solid substrates, 12 studies demonstrating BK-based nanostructured assemblies are still lacking.…”