A new solid-phase synthesis strategy builds ring-shaped peptides with a reactive backbone amine, enabling efficient production of lipidated cyclic and bicyclic antimicrobial peptides.
3- to 13-mer macrocyclesThe method works across a wide range of peptide ring sizes using standard synthesis equipment
What the researchers found
Researchers developed a new way to build ring-shaped (macrocyclic) peptides directly on solid-phase synthesis supports. The key innovation is that the ring closure creates a secondary amine in the peptide backbone that remains chemically reactive — meaning you can keep building on the peptide after cyclization. This enabled the synthesis of both cyclic and bicyclic peptides ranging from 3 to 13 amino acids, and the method was demonstrated by making lipidated antimicrobial peptide variants.
Why it matters
Cyclic peptides are more drug-like than linear ones — they're more stable, more selective, and better at crossing cell membranes. But making them is hard, especially when you want to add lipid chains (lipidation) that further improve drug properties. This method solves that problem by leaving a reactive handle inside the ring that allows further chemistry. It could accelerate the development of next-generation antimicrobial peptides and other cyclic peptide drugs.
The numbers in context
3- to 13-mer macrocycles · compatible with standard Fmoc/tBu SPPS · cyclic and bicyclic peptides produced · lipidated antimicrobial peptide variants demonstrated
How the study worked
Organic chemistry method development. The researchers used intramolecular halide substitution by a diamino acid during standard solid-phase peptide synthesis (Fmoc/tBu SPPS) to form macrocyclic peptides. The resulting endocyclic secondary amine was then acylated to continue synthesis, producing lipidated cyclic and bicyclic antimicrobial peptides.
Who was studied
Not applicable (chemical synthesis methodology study)
What this study cannot tell us
This is a synthesis methodology paper — no biological activity data is presented for the antimicrobial peptides produced. The approach was demonstrated on a limited range of peptide sizes. Scalability and compatibility with all amino acid sequences were not fully explored.
How to read the evidence
Preliminary — this is a chemistry methodology paper demonstrating a new synthesis approach. While the chemistry works, no biological testing of the resulting peptides is reported. The value lies in enabling future biological studies, not in direct therapeutic evidence.
When this study was published
Published in 2015. The cyclic peptide synthesis field has continued to advance, but the core approach described here — on-resin macrocyclization with a reactive backbone amine — remains a useful strategy in the peptide chemist's toolkit.
The bigger picture
The growing crisis of antibiotic resistance has pushed researchers toward antimicrobial peptides as alternatives to traditional antibiotics. But turning these peptides into viable drugs requires making them more stable and potent — which often means cyclization and lipidation. This synthesis method removes a major bottleneck in that process, potentially enabling medicinal chemists to rapidly explore libraries of cyclic and bicyclic antimicrobial peptide variants to find the best drug candidates.
Questions still open
- How do the lipidated cyclic antimicrobial peptides produced by this method perform against drug-resistant bacteria?
- Can this synthesis approach scale to produce the quantities needed for preclinical testing?
- Does the endocyclic secondary amine affect the biological activity or stability of the final peptide products?
Common questions
Why are ring-shaped peptides better as drugs than straight-chain ones?
What does lipidation do for antimicrobial peptides?
Read the original research
Peptide macrocycles featuring a backbone secondary amine: a convenient strategy for the synthesis of lipidated cyclic and bicyclic peptides on solid support.
Organic letters, 17(10), 2502-5
Citation
Oddo, Alberto; Münzker, Lena; Hansen, Paul R. (2015). Peptide macrocycles featuring a backbone secondary amine: a convenient strategy for the synthesis of lipidated cyclic and bicyclic peptides on solid support.. Organic letters, 17(10), 2502-5. https://doi.org/10.1021/acs.orglett.5b01026