A mass spectrometry workflow targets cyclic peptides and finds two new ones in a marine sponge

Researchers at Shanghai Jiao Tong University School of Medicine, with a co-author at Qilu University of Technology (Shandong Academy of Sciences), reported in Analytical Chemistry, published online on 7 October 2026, an integrated mass spectrometry strategy they call IMSS for finding cyclic peptides in marine organisms. [1]

Why cyclic peptides are hard to find

Cyclopeptides are a structurally diverse class of natural products, but the authors note that they remain analytically challenging because they look very similar to one another, occur in low amounts and sit inside complex biological mixtures. [1] Earlier computational work made a similar point: a lack of analysis pipelines suited to these ring-shaped compounds has limited how many of them can be identified from mass spectra. [2]

Four steps in one workflow

IMSS links four stages so that detection, annotation and isolation run as a single process. [1]

1. Targeted scanning. The instrument runs multiplexed diagnostic neutral-loss and precursor-ion scans built around the six residues the team found most often in 16 reference cyclopeptides: proline, isoleucine/leucine, valine, tyrosine, phenylalanine and tryptophan. [1] 2. De novo checking. Candidate spectra are validated with de novo sequencing using CycloNovo, [1] an algorithm published in 2020 that reconstructs cyclopeptide sequences directly from spectra using de Bruijn graphs, the same graph approach used in DNA sequence assembly. [2] 3. Two-way dereplication. Candidates are compared both through GNPS molecular networking and against a curated library of 538 marine cyclopeptides, so that already-known compounds can be set aside. [1] GNPS is an open-access knowledge base for sharing raw, processed and identified tandem mass spectrometry data, with community-curated reference libraries. [3] 4. Triggered purification. An MS-triggered automated purification step then isolates the targets the earlier stages have flagged. [1]

Results from one sponge

Applied to the marine sponge Phakellia fusca, IMSS produced 23 candidate cyclopeptides. [1] It also guided the targeted purification of two previously unknown cyclooctapeptides, named phakellicyclins A and B, which contain the rare residues dioxindolylalanine and β-3-oxindolylalanine, respectively. [1]

Why it matters for peptide analysis

The paper is a methods study. The authors describe IMSS as a robust and reproducible mass spectrometry workflow for the targeted discovery of marine cyclopeptides rich in proline and isoleucine/leucine, and say it could be adapted to other cyclopeptide classes. [1] For laboratories that work with peptide mixtures, it is an example of combining targeted scan modes, sequence-level validation and library matching before committing time to isolation, so that effort goes to compounds that are actually new. The full experimental details are behind the journal's paywall; the figures above come from the published abstract.

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