G protein–coupled receptors (GPCRs) are the largest family of membrane proteins and key regulators of physiological processes such as metabolism, immunity, sensory perception, and neurological function. Their therapeutic importance is underscored by the fact that more than one-third of approved drugs act on GPCRs. Despite this success, many peptide-binding GPCRs remain underexplored, in part because rational ligand design has historically been constrained by limited structural information. Recent years have brought significant progress. Cryo-electron microscopy has delivered high-resolution structures of previously elusive GPCR–ligand complexes, while artificial intelligence tools such as AlphaFold and RoseTTAFold have enabled accurate modelling of receptors without close homologues. To build on this momentum, this Research Topic will concentrate on studies of GPCR structures reported from 2020 onwards, using these new insights to enable rational design of synthetic peptides and peptide–small molecule conjugates with therapeutic potential.
The goal of this Research Topic is to showcase how recent GPCR structural insights (2020 onwards) can be systematically harnessed for the rational design of synthetic peptide ligands and peptide–small molecule conjugates. Central to this theme is the application of structure–activity relationship (SAR) studies that directly link structural modifications to biological outcomes, enabling optimisation of stability, selectivity, and pharmacokinetics.
A special focus will be placed on therapeutic discovery, where rationally designed peptide modalities can address high-priority clinical challenges. Examples include anti-obesity agents targeting GLP-1 receptors, peptide modulators of chemokine receptors in oncology, and conjugates designed to influence neurological GPCR pathways. By bringing together expertise from structural biology, chemistry, and pharmacology, this initiative seeks to highlight how these rational design strategies can accelerate the translation of structural knowledge into tangible therapeutic leads.
This Research Topic welcomes manuscripts that leverage structural insights reported since 2020 to advance peptide and peptide–small molecule conjugate discovery for GPCRs. We encourage studies that integrate cryo-EM, X-ray crystallography, or AI-predicted models into rational design workflows. Relevant themes include: Structure-guided strategies for peptide and hybrid (peptide-small molecule) ligand development.
Systematic SAR studies linking structural modifications to pharmacological outcomes.
Hybrid peptide–small molecule ligands that combine specificity with improved drug-like properties
Computational and AI-based approaches in predicting ligand–receptor interactions.
Case studies highlighting therapeutic applications in obesity (GLP-1), oncology (chemokine receptors), and neurological disorders.
Perspectives on challenges and opportunities in translating structural advances into drug discovery.
We welcome original research, reviews, mini-reviews, and perspectives. Together, these contributions will provide a timely overview of how recent structural advances are driving innovation in GPCR-targeted peptide therapeutics.
Article types and fees
This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:
Brief Research Report
Data Report
Editorial
FAIR² Data
FAIR² DATA Direct Submission
General Commentary
Hypothesis and Theory
Methods
Mini Review
Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.
Article types
This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:
Brief Research Report
Data Report
Editorial
FAIR² Data
FAIR² DATA Direct Submission
General Commentary
Hypothesis and Theory
Methods
Mini Review
Opinion
Original Research
Perspective
Review
Systematic Review
Technology and Code
Keywords: GPCRs, Rational Drug Design, Peptide Therapeutics, Peptide–Small Molecule Conjugates, SAR
Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
