Biased signaling at class B GPCRs opens door to safer, more effective peptide drug design | Research

The takeaway

Class B GPCRs (15 peptide hormone receptors including GLP-1R, CGRP-R, and PACAP receptors) can be targeted with biased agonists/antagonists that activate specific signaling pathways, enabling drugs with enhanced efficacy and reduced side effects.

Pathway-selective drug design
Biased signaling at class B GPCRs enables "designer" peptide drugs that activate therapeutic pathways while avoiding side-effect-causing ones—the future of GLP-1 and CGRP therapeutics

What the researchers found

Class B GPCRs: 15 peptide hormone receptors. Recent approvals: migraine (CGRP), diabetes (GLP-1), obesity. Biased signaling enables pathway-selective drugs. Designer drugs: enhanced efficacy, reduced side effects. Applicable to GLP-1R, CGRP-R, PACAP receptors, and others.

Why it matters

Understanding that GLP-1 and CGRP receptors can be activated in pathway-selective ways opens doors to next-generation drugs that maximize therapeutic effects while minimizing side effects.

How the study worked

Narrative review of biased signaling pharmacology at class B GPCRs, covering approved therapeutics and drug development.

What this study cannot tell us

Narrative review. Biased signaling measurement is complex. Translation from in vitro bias to clinical outcomes is uncertain. Few biased drugs have reached clinical testing.

How to read the evidence

Narrative review of established pharmacological principles with emerging applications.

When this study was published

Published in 2025.

The bigger picture

Biased signaling is the frontier of peptide drug design. Rather than activating all downstream pathways (causing side effects), future drugs will activate only the beneficial ones—a precision pharmacology approach.

Questions still open

Which signaling pathway is most important for GLP-1 weight loss vs GI side effects?
Can biased GLP-1 agonists reduce nausea while maintaining efficacy?
Will CGRP receptor biased antagonists provide migraine relief without immune effects?

Common questions

What is biased signaling?

When a drug activates a receptor, it can trigger multiple downstream pathways. Biased signaling means designing drugs that activate only the beneficial pathways while avoiding the ones that cause side effects. For GLP-1 drugs, this could mean weight loss without nausea.

Could this make GLP-1 drugs better?

Yes. Current GLP-1 drugs activate all signaling pathways at the receptor, including those causing nausea and vomiting. Biased agonists could be designed to activate the appetite-suppressing pathway while avoiding the nausea pathway—potentially transforming tolerability.

Read the original research

Where are we now? Biased signalling of Class B G protein-coupled receptor-targeted therapeutics.

Pharmacology & therapeutics, 270, 108846

View on PubMed ↗Publisher’s paper ↗

Citation

Tasma, Zoe; Garelja, Michael L; Jamaluddin, Aqfan; Alexander, Tyla I; Rees, Tayla A. (2025). Where are we now? Biased signalling of Class B G protein-coupled receptor-targeted therapeutics.. Pharmacology & therapeutics, 270, 108846. https://doi.org/10.1016/j.pharmthera.2025.108846