Swapping one carbon for one nitrogen atom in the backbone of GLP-1 and GIP peptides made them completely resistant to the enzyme DPP4 that normally destroys them, while retaining full potency at their receptors.
1 atom changefrom carbon to nitrogen in the peptide backbone conferred complete DPP4 resistance while retaining full receptor agonist potency
What the researchers found
A single aza-amino acid substitution (carbon → nitrogen) at the second position from the N-terminus made GLP-1 and GIP peptide agonists completely resistant to DPP4 degradation while retaining full potency and efficacy at their respective receptors (GLP-1R and GIPR).
Molecular dynamics simulations confirmed that aza-amino acids can adopt the same conformational space as natural amino acids when the peptide binds its receptor. The modification was successfully applied to semaglutide and a dual GLP-1R/GIPR agonist, demonstrating it works as a viable alternative to existing DPP4 resistance strategies and offers additional structural variation that may influence downstream signaling.
Why it matters
Current GLP-1 drugs like semaglutide require complex chemical modifications (fatty acid chains, amino acid substitutions) to resist DPP4 breakdown. This study shows that a single atom swap achieves the same protection with minimal disruption to the peptide's natural structure. This approach could simplify the design of next-generation peptide drugs and may create new opportunities for fine-tuning their pharmacological properties.
How the study worked
The researchers synthesized GLP-1 and GIP peptide analogs incorporating aza-amino acids — bioisosteric replacements where backbone carbon is swapped for nitrogen. They tested DPP4 resistance in enzyme assays, measured receptor activation potency and efficacy, and used molecular dynamics simulations to understand how the structural modification affects peptide conformation and receptor binding.
What this study cannot tell us
This is a medicinal chemistry and in vitro study — no animal or human pharmacokinetic data are presented. While the modified peptides retained receptor potency, their actual in vivo stability, bioavailability, and therapeutic efficacy need to be demonstrated. The impact of the aza-amino acid modification on downstream signaling pathways beyond receptor activation is noted as a possibility but not fully characterized.
How to read the evidence
This is a preclinical medicinal chemistry study with in vitro receptor activation assays and computational modeling. Published in Angewandte Chemie, a top chemistry journal, the work is rigorous but does not include in vivo or clinical data.
When this study was published
Published in 2024 in Angewandte Chemie, this is a very recent study presenting a novel chemical approach to peptide drug design that could influence next-generation GLP-1 therapeutics.
The bigger picture
The GLP-1 drug market is worth billions and growing rapidly, with intense competition to develop improved formulations. This aza-amino acid approach represents a fundamentally new strategy for peptide drug stabilization that could apply not just to GLP-1 and GIP but to any peptide drug susceptible to protease degradation. It could enable a new generation of simpler, more tunable peptide therapeutics.
Questions still open
- Does the aza-amino acid modification affect the in vivo pharmacokinetics and duration of action of these peptides?
- Could this approach be combined with existing modifications like fatty acid acylation for even longer-acting formulations?
- Does the structural change influence biased agonism or other signaling properties at GLP-1R and GIPR?
Common questions
Why do GLP-1 drugs need protection from DPP4?
Could this lead to better diabetes or weight loss drugs?
Read the original research
Potent and Protease Resistant Azapeptide Agonists of the GLP-1 and GIP Receptors.
Angewandte Chemie (International ed. in English), 63(49), e202410237
Citation
Dinsmore, Tristan C; Liu, Jamie; Miao, Jiayuan; Ünsal, Özge; Sürmeli, Damla; Beinborn, Martin; Lin, Yu-Shan; Kumar, Krishna. (2024). Potent and Protease Resistant Azapeptide Agonists of the GLP-1 and GIP Receptors.. Angewandte Chemie (International ed. in English), 63(49), e202410237. https://doi.org/10.1002/anie.202410237