Open AccessSynthetic Natural Product Inspired Cyclic Peptides
Author(s) -
Matthew A. Hostetler,
Chloe Smith,
Samantha Nelson,
Zachary L. Budimir,
Ramya Modi,
Ian Woolsey,
Autumn M. Frerk,
Braden Baker,
J. Stephen Gantt,
Elizabeth I. Parkinson
Publication year - 2021
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.1c00641
Subject(s) - natural product , cyclic peptide , peptide , nonribosomal peptide , computational biology , drug discovery , combinatorial chemistry , biochemistry , gene , peptide biosynthesis , chemical biology , small molecule , biosynthesis , combinatorial synthesis , cyclase , chemistry , biology , enzyme , ribosome , rna
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 ( S ynthetic Na tural P roduct Inspired Cyclic P eptides), 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 allowed for identification of 131 novel pNPs. Fifty-one diverse pNPs were synthesized using solid phase peptide synthesis and solution-phase cyclization. Antibacterial testing revealed 14 pNPs with antibiotic activity, including activity against multidrug-resistant Gram-negative bacteria. Overall, SNaPP demonstrates the power of combining bioinformatics predictions with chemical synthesis to accelerate the discovery of bioactive molecules.