biostudies-literatureHostetler MANational Cancer InstituteNCI NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS2604-2611https://www.ebi.ac.uk/biostudies/studies/S-EPMC8610019biostudies-literatureUnknown16(11)Natural products are a bountiful source of bioactive molecules. Unfortunately, discovery of novel bioactive natural products is challenging due to cryptic biosynthetic gene clusters, low titers, and arduous purifications. Herein, we describe SNaPP (Synthetic Natural Product Inspired Cyclic Peptides), a method for identifying NP-inspired bioactive peptides. SNaPP expedites bioactive molecule discovery by combining bioinformatics predictions of nonribosomal peptide synthetases with chemical synthesis of the predicted natural products (pNPs). SNaPP utilizes a recently discovered cyclase, the penicillin binding protein-like cyclase, as the lynchpin for the development of a library of head-to-tail cyclic peptide pNPs. Analysis of 500 biosynthetic gene clusters alloweACS chemical biologySynthetic Natural Product Inspired Cyclic Peptides.PMC8610019P30 CA023168R35 GM1380021R35GM138002-01Frerk ABudimir ZSmith CNelson SModi RHostetler MAGantt JWoolsey IParkinson EIBaker BfalseSynthetic Natural Product Inspired Cyclic Peptides.Natural products are a bountiful source of bioactive molecules. Unfortunately, discovery of novel bioactive natural products is challenging due to cryptic biosynthetic gene clusters, low titers, and arduous purifications. Herein, we describe SNaPP (Synthetic Natural Product Inspired Cyclic Peptides), a method for identifying NP-inspired bioactive peptides. SNaPP expedites bioactive molecule discovery by combining bioinformatics predictions of nonribosomal peptide synthetases with chemical synthesis of the predicted natural products (pNPs). SNaPP utilizes a recently discovered cyclase, the penicillin binding protein-like cyclase, as the lynchpin for the development of a library of head-to-tail cyclic peptide pNPs. Analysis of 500 biosynthetic gene clusters allowe2021-01-01T00:00:00Z2021 Nov2026-07-14T15:04:32.704Z2025-04-04T12:10:38.648ZS-EPMC86100193469917010.1021/acschembio.1c00641