Amping Up Receptor Balance and Bias: Fine Tuning of Unimolecular Multiagonists

Unimolecular multiagonists integrating GLP-1R/GIPR, and increasingly GCGR agonism, have altered the landscape of peptide therapeutics for metabolic syndrome. This progress has shifted the field from optimizing individual ligands to engineering defined receptor selectivity (balance) and, in some cases, pathway-selective signaling (bias) within a single-peptide scaffold. Despite this momentum, tuning 'balance' and 'bias' remains difficult because small sequence changes can have receptor-dependent, nonintuitive effects, and meaningful retuning often requires wholesale scaffold redesign. Here, we implement a systematic strategy based on simple N-terminal chemical modifications across dual- and triagonist templates to decouple these variables. Because the peptide N-terminus is buried within the membrane-embedded transmembrane core of class B GPCRs, localized chemical edits at this site provide a sensitive lever for reweighting receptor activation. These minimal changes can alter signaling preference without loss of efficacy, expanding the design grammar and offer rapid tuning of potency, efficacy, and bias.