Nonribosomal peptides and similar natural products have an unparalleled track record in pharmacology that began with the discovery of penicillin. Indeed, nine of the top 20 best-selling drugs were either inspired by or derived from such natural products, said Nuno Bandeira, a researcher with the University of California, San Diego, in La Jolla. However, discovery of such compounds for medical purposes is complicated because there are no methods available for high-throughput sequencing of nonribosomal peptides.At a Research in Computational Molecular Biology meeting held in Singapore in March, Bandeira and colleagues from the San Diego and Santa Cruz campuses of the University of California reported a mass-spectrometry-based approach to sequencing nonribosomal peptides. They showed that automated de novo sequencing of cyclic nonribosomal peptides is possible using a combination of algorithmic and experimental mass spectrometry techniques.Researchers have reported a multistage mass spectrometry technique that uses a combination of algorithmic and experimental methods for high-throughput nonribosomal peptides. The technique could contribute to discovery of new drugs based on this type of peptide.Although multistage mass spectrometry recently gained acceptance as a tool for nonribosomal peptide identification, Bandeira explained, most of the studies thus far have been limited to two stages. In its experiments, his group used multistage mass spectrometry for de novo peptide sequencing and sampling of as many as five stages. Such use, combined with heuristic algorithms for data analysis, allowed the researchers to reconstruct cyclic peptides from a single spectrum and to score them against the remaining spectra.The study served as a proof of concept, Bandeira said, demonstrating that the combination of experimental and computational techniques can solve the problem efficiently. He also noted that “an efficient and automated way to sequence [nonribosomal peptides] will immediately benefit all searches for natural compounds of medical importance as well as studies of still poorly understood mechanisms of the nonribosomal peptide synthesis.” When DNA sequencing is not available, biologists typically call on either Edman degradation or tandem mass spectrometry for sequencing ribosomal peptides. However, neither of these techniques can be applied successfully with nonribosomal peptides because they differ considerably. The described technique therefore addresses important needs in both drug discovery and nonribosomal peptide research.The researchers hope that the study will resolve what they call a catch-22 when it comes to using mass spectrometry for nonribosomal peptide interpretation. On the one hand, very little mass spectrometry data is available for nonribosomal peptides because information on how to interpret the spectra automatically is limited. On the other hand, the relative dearth of mass spectrometry data for nonribosomal peptides slows development of algorithms needed for interpretation. With the current study, they hope to break “this vicious cycle.”