Lasso peptides
Bacterially produced peptides physically threaded through their own macrolactam ring like a slipknot, giving protease and heat stability that no ordinary peptide has — currently the most interesting new antibiotic scaffold in years.
Also known as threaded lasso scaffolds, microcin J25, class II RiPPs, lariocidin
Animal data only — Rodent or other animal studies. Dose translation to humans is genuinely uncertain.
Strong structural biology and in-vitro antimicrobial data, with lariocidin showing efficacy in a mouse infection model and evading known resistance mechanisms. Nothing in this class has entered human trials as of mid-2026. The excitement is about the scaffold and about a genuinely new antibiotic binding site, not about an available drug.
How it works
A lasso peptide is formed when an isopeptide bond between the N-terminal amine and a downstream aspartate or glutamate creates a small ring, and the C-terminal tail is then threaded through that ring and sterically trapped by bulky residues acting as plugs. The result is a mechanically interlocked molecule that resists proteases, denaturants and temperatures above 90 C. The bioactivities are unusually diverse for one structural class: microcin J25 blocks bacterial RNA polymerase by plugging its secondary channel, lariocidin binds the small ribosomal subunit at a site no existing antibiotic uses and is active against multidrug-resistant Gram-negative pathogens including strains resistant to everything else, sviceucin and siamycin restore vancomycin sensitivity in VRE, and other family members are antagonists at the glucagon receptor, endothelin type B receptor and myosin light chain kinase. Engineering interest has accelerated because machine-learning models like LassoESM can now predict which precursor sequences a given cyclase will accept, unlocking sequences that could not previously be made.
Targets: Bacterial RNA polymerase secondary channel, Bacterial ribosome (lariocidin), Glucagon receptor (select members), Endothelin type B receptor (select members)
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| No clinical protocol existsNot applicable. | — | not established | intravenous |
- · No lasso peptide has completed a human trial. Lariocidin is the furthest along as a preclinical antibacterial lead and a more stable variant has been nominated for development. There is no consumer product here and nothing to dose.
Cycling
Not applicable.
Pharmacology
- Half-life
- Not established for any clinical candidate; the scaffold's protease resistance implies unusually long metabolic stability for a peptide.
- Onset
- Not applicable — no clinical candidate has a defined onset.
- Routes
- intravenous, oral, subcutaneous
- Molecule
- Ribosomally synthesised and post-translationally modified peptide (RiPP) with a mechanically interlocked lariat topology, typically 15-24 residues
Handling
- Diluent
- Not applicable
- Lyophilised
- Room temperature is tolerated; thermal stability is the class's signature property.
- Reconstituted
- Refrigerated.
Mixing
Lasso peptides cannot be made by ordinary solid-phase synthesis — the threaded topology requires the biosynthetic cyclase enzyme, so production is by fermentation or heterologous expression.
Side effects
- commonUnknown— No human exposure data exist for any member of this class.
Do not use if
- Human use outside formal research.
What to monitor
- · Not applicable.
Legal status
Preclinical research materials only. No approved product.
References
- Jangra et al. 2025, Nature — lariocidin, a lasso peptide antibiotic acting on the ribosome (preclinical)
- Hegemann et al. 2015, Accounts of Chemical Research — lasso peptides as an intriguing class of bacterial natural products (review)
Mechanism in depth
Ribosomally synthesised bacterial peptides with a threaded lariat topology - the tail passes through a macrolactam ring and is sterically trapped. The knot is mechanical rather than covalent, and it confers extreme thermal and proteolytic stability. Several have antibacterial activity, and the scaffold is of interest for engineering.
What usually goes wrong
As with cyclotides, remarkable stability gets described as though it were clinical promise. Stability solves one problem out of several, and none of the others - selectivity, spectrum, manufacturability - is solved by the topology.
Receptor targets
- Varies; several target bacterial RNA polymerase
Antibacterial activity for some members
Genuinely uncertain
- No clinical-stage lasso peptide therapeutic.
- Heterologous production remains difficult, limiting supply for study.