Can a new discovery usher in a new generation of GLP-1 peptides – the science behind weight loss drugs? From such a discovery, can we expect a more targeted version of popular drugs such as Ozempic?
These questions may well arise through new research, which comes from the University of Utah. Here researchers have found that if they “tie off” radical enzymes, it can help power a makeover in these peptides. According to one of the authors, big-pharma’s GLP-1 backbones are already excellent; what we’re adding is a clean, late-stage enzymatic step that can ‘tie off’ the C-terminus and make those molecules work even harder.
Glucagon-like peptide-1 (GLP‑1)–pathway agonists such as semaglutide and newer multi‑agonists have transformed care for obesity and diabetes, yet drug firms still wrestle with durability, tissue targeting, and signal “bias.”
Semaglutide is a prescription medication primarily used for weight loss and the management of type 2 diabetes. It functions as a GLP-1 receptor agonist, which helps regulate appetite by binding to GLP-1 receptors in the brain, leading to reduced hunger and food intake.
While processes like macrocyclization, tying part of a peptide into a ring, can shield drugs from degradation and favour bioactive shapes, yet this form of conventional chemistry can be costly and hard to apply late in development.
Radical enzyme
A research team at Sethera Therapeutics and the Bandarian Lab at the University of Utah have shown that a radical enzyme can “tie off” therapeutic peptides into compact rings without the usual leader‑sequence requirements.
The researchers report about a biocatalytic shortcut: an enzyme that stitches a precise thioether bond at peptide C‑termini without the leader tags that many peptide‑modifying enzymes usually require. In analytical readouts, the GLP‑1‑like analogues exhibited hallmark shifts indicative of ring formation after enzymatic processing.
The work centres on radical S‑adenosyl‑L‑methionine (rSAM) maturases from the RiPP (ribosomally synthesized and post‑translationally modified peptide) family. RiPP enzymes typically recognize an N‑terminal “leader” sequence via an RRE (RiPP recognition element) for specific binding.
Here, the team demonstrated “leader‑independent” activity: their process cleanly macrocyclized GLP‑1‑pathway analogs engineered with a C‑terminal cross-linking motif, modifying the linear peptides under mild conditions. The enzyme did so even on substrates containing non‑canonical residues common to marketed incretins, underscoring broad tolerance.
New Ozempic?
While most RiPP maturases need leader/RRE interactions, the Sethera and University of Utah group modified a chimeric substrate bearing an unrelated leader and still showed activity when the RRE domain was deleted, indicating that neither canonical leader binding nor the intact RRE is strictly required.
This minimal constraint appears to reduce to a local Cys–Xⁿ–Asp/Glu motif at the cyclization site, enabling “plug‑and‑play” macrocycle installation with little re‑engineering.
For therapeutics, the C‑terminal ring can do more than tie off the chain. By rigidifying the tail, it may enhance receptor affinity or bias signalling; by capping the C‑terminus, it can block proteases; and because the enzymatic process accepts diverse sequences, the ring itself can be designed as a modular “handle” to engage albumin, transporters, or disease‑related receptors—routes to longer half‑life, tissue targeting, or selective activity.
Together, these data suggest a general, late‑stage biocatalytic pathway to next‑generation incretins and other peptide drugs.
The study appears in the journal ACS Bio & Med Chem Au The study is titled “Leader-Independent C-Terminal Modification by a Radical S-Adenosyl-l-methionine Maturase Enables Macrocyclic GLP-1-Like Peptides.”
