May 29, 2023

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Development of Allosteric Regulators of GPCR Bias Signal

Development of Allosteric Regulators of GPCR Bias Signal


Development of Allosteric Regulators of GPCR Bias Signal.  GPCR (Gprotein-coupled receptors) is currently the most successful FDA-approved drug target family, but classic GPCR agonists and antagonist ligands cannot solve key issues such as selectivity.

In recent years, the appearance of biased allosteric modulators (BAM) has brought new breakthroughs in GPCR drug discovery. Compared with Orthosteric ligand (Orthosteric ligand), BAM by targeting the allosteric site (Allosteric site) outside the receptor’s orthotic pocket to play a pathway-specific regulation of receptor signal transduction, and then to achieve physiological The fine adjustment of activities and the development of safer and more selective treatments have provided great help.

Development of Allosteric Regulators of GPCR Bias Signal Development of Allosteric Regulators of GPCR Bias Signal


Table 1. Summary of BAMs that have been proven to work

ReceptorReceptor  classBiasing  modulator classBiasing  modulatorAgonistReported  biasPotential  therapeutic utility
Bias toward G  protein coupling or G protein subtype preference
C-X-CChemokine receptor type  4 (CXCR4)Class  APepducinATI  2341SDF-1Gi  > β-arrestin, GRK2,HIV,  leukemias
GRK3  >> G13
Prostaglandin  F2α (PGF2α)receptorClass  ASmall  moleculePDC113.824PGF2αGq  > G12Preterm  labor
Melanocortin  receptors 3, 4,and 5 (MC3-5R)Class  ASmall  moleculeFenoprofenαMSHERK1/2  > cAMPInflammatory arthritis,  obesity
Free  fatty acid receptor 2 (FFAR2)Class  ASmall  moleculeAZ  1729C3Gi  > Gq/11Metabolic  disorders
Follicle stimulating hormone  receptor (FSHR)Class  ASmall  moleculeThiazolidinone  analogsFSHGi  > GsInfertility
δ-opioid  receptorClass  ASmall  moleculeBMS  986187Leu-enkephalin,  SNC80, and TAN67G  protein (general, GTPγS) >Chronic  pain, depression
Calcium  sensing receptorClass  CSmall  moleculeAC  265347Ca2+oIP1,  ERK1/2 > Ca2+Hyper-parathyroidism
R,R-calcimimetic  BCa2+oIP1,  ERK1/2 > Ca2+
Bias toward  β-arrestin coupling
Neurotensin  receptor 1 (NTSR1)Class  ASmall  moleculeML314NTS,  NTS8–13β-Arrestin2  > Gq/Ca2+Addiction,  psychiatric disorders
SBI-553NTS,  NTS8–13β-Arrestin2  > Gq/Ca2+
β2-Adrenergic  receptor (β2AR)Class  APepducinICL1–9ICYPβ-Arrestin  > GsMyocardial  infarction, heart failure
Cannabinoid  receptor type 1 (CB1R)Class  ASmall  moleculeORG27569CP55940β-Arrestin1  > G protein (general, GTPγS)Obesity,  pain, neurodegenerative disorders
Pyrimidinyl  biphenylureasCP55940β-Arrestin1/2  > G protein
C-X3-Cchemokine receptor 1 (CX3CR1)Class  ASmall  moleculeAZD8797Fractalkineβ-Arrestin  > G protein (general, GTPγS)Atherosclerosis,  metabolic disorders

Current studies have shown that after GPCR receptors are activated by binding bias ligands, their conformational changes can couple to different effector proteins and participate in related signal pathways. GPCR-coupled effector proteins are divided into two categories: G protein (Gs, Gi/o, Gq, G12, etc.) and Arrestin (β-arrestin1, β-arrestin2). Bias ligand actually relatively enhances the receptor’s ability to couple to a specific downstream effector protein to play a regulatory role on the bias signal. Based on the effector proteins coupled downstream of the receptor, the bias ligands that have been discovered so far can be divided into G protein bias ligands (G proteins vs. Arrestin), Arrestin bias ligands (Arrestin vs. G proteins), and specific G proteins. Protein subtype bias (such as Gi vs. Gs). From the perspective of kinetics, a receptor actually has multiple active conformations, and BAM stabilizes one specific active conformation.

Development of Allosteric Regulators of GPCR Bias Signal

From a thermodynamic point of view (as shown in the figure above), GPCRs can be divided into two categories, one is the two-state system receptor (m = 2, such as cannabinoid, etc.). The two states corresponding to this type of receptor may be full-on or full-off, so it is very difficult to use the orthomorphic site to control the bias signal; the other type is the receptor with multiple receptor states (m= 4, such as Cytokine, etc.), the probability of realizing a bias signal through orthomorphic sites is lower. This analysis shows that for many GPCRs, the realization of bias signal regulation based on normal sites is very limited, and it may be more effective to design BAMs targeting allosteric sites.

Development of Allosteric Regulators of GPCR Bias Signal

From an allosteric point of view, GPCR has many endogenous regulatory factors (such as G  proteins, β-arrestins, ions, etc.), so a receptor may have multiple allosteric sites, and the bias signal can also be affected by these endogenous Molecular allosteric regulation (such as: GPCR accessory protein MRAP2 regulates the bias signal of ghrelin receptor GHSR1a). In addition to endogenous regulators, a variety of exogenous regulators (including small molecules, peptides and polypeptides, etc.) have also been found. In theory, allosteric modulators lack intrinsic activity and have no ability to activate receptors in the absence of agonists. However, there are exceptions. For example, individual BAMs can be used as biased allosteric agonists (ago-BAMs) alone or as biased allosteric agonists (ago-BAMs). Bias modifiers play a specific role in signaling pathways (Table 1).

BAM has good characteristics of allosteric and biased ligands at the same time, so it has many advantages in treatment:

1. Increase receptor subtype selectivity and pathway specificity: BAM targets low-conservative allosteric sites, which can achieve targeted regulation for specific receptors of the same family subtype; in addition, bias ligands can also be selected Sexually participate in treatment-related signal pathways;

2. Targeted regulation of GPCRs that are “difficult to target”: Many GPCRs have restricted the development of related regulators due to their unique orthomorphic site geometry and abnormally high endogenous ligand occupancy rate. The emergence of BAM is for this reason. The regulation of GPCR-like activity brings hope;

3. Retain the physiological activity of the body: BAM lacking intrinsic activity can retain the body activation of the receptor by the endogenous ligand, reducing the side effects caused by the complete blockade of the signal pathway;

4. Combination therapy with saturation of effect and effect: The theoretical dependence of allosteric modulators on endogenous ligands leads to the “ceiling effect” of allosteric ligands, which can ensure the safety of the target when the dose is excessive; in addition, it can also be achieved Combination therapy of BAM and orthomorphic drugs, using BAM to increase the effect of orthomorphic drugs;

Although BAM has great potential for GPCR targeted therapy, it also has some shortcomings worthy of our attention. For example, bias agonists activate receptors in an unnatural way and may produce unexpected biological effects. Not only that, Some allosteric modulators target membrane receptor interface sites with lower receptor affinity and water solubility, which will reduce the potency and water solubility of the allosteric modulator.


In general, biased allosteric modulators are a new class of GPCR ligands, which can exert pathway-specific effects on receptor signaling pathways, thereby changing the physiological behavior of GPCRs. BAMs increase the receptor subtypes and pathway selectivity of ligands, provide an opportunity to develop safer and more effective treatments and to target the previously “difficult to target GPCRs”, creating a new situation for GPCR drug discovery.




(source:internet, reference only)


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