ArticleNature communications2022
Lapcin, a potent dual topoisomerase I/II inhibitor discovered by soil metagenome guided total chemical synthesis.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Metagenomics and its impact on environmental and therapeutic microbiology.Archives of microbiology · 2025Review
- Structural Mechanisms of Topoisomerase-Targeting Drugs.Annual review of biochemistry · 2025Review
- Marine-derived new peptaibols with antibacterial activities by targeting bacterial membrane phospholipids.Acta pharmaceutica Sinica. B · 2025Article
- Synthetic-bioinformatic natural product-inspired peptides.Natural product reports · 2025Review
- The Imidazacridine Derivative LPSF/AC-05 Induces Apoptosis, Cell Cycle Arrest, and Topoisomerase II Inhibition in Breast Cancer, Leukemia, and Lymphoma.Current cancer drug targets · 2025Article
- Cinnamosyn, a Cinnamoylated Synthetic-Bioinformatic Natural Product with Cytotoxic Activity.Organic letters · 2024Article
- Tapcin, an In Vivo Active Dual Topoisomerase I/II Inhibitor Discovered by Synthetic Bioinformatic Natural Product (Syn-BNP)-Coupled Metagenomics.Angewandte Chemie (International ed. in English) · 2024Article
- Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond.Beilstein journal of organic chemistry · 2024Article
- Structural advances toward understanding the catalytic activity and conformational dynamics of modular nonribosomal peptide synthetases.Natural product reports · 2023Review
- Article
- Next-generation synthetic biology approaches for the accelerated discovery of microbial natural products.Engineering microbiology · 2023Review
- Regulated Expression of an Environmental DNA-Derived Type II Polyketide Gene Cluster in Streptomyces Hosts Identified a New Tetracenomycin Derivative TCM Y.Current microbiology · 2022Article
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Authors and funding
5 authors.
Funding
Abstract
In natural product discovery programs, the power of synthetic chemistry is often leveraged for the total synthesis and diversification of characterized metabolites. The synthesis of structures that are bioinformatically predicted to arise from uncharacterized biosynthetic gene clusters (BGCs) provides a means for synthetic chemistry to enter this process at an early stage. The recent identification of non-ribosomal peptides (NRPs) containing multiple ρ-aminobenzoic acids (PABAs) led us to search soil metagenomes for BGCs that polymerize PABA. Here, we use PABA-specific adenylation-domain sequences to guide the cloning of the lap BGC directly from soil. This BGC was predicted to encode a unique N-acylated PABA and thiazole containing structure. Chemical synthesis of this structure gave lapcin, a dual topoisomerase I/II inhibitor with nM to pM IC50s against diverse cancer cell lines. The discovery of lapcin highlights the power of coupling metagenomics, bioinformatics and total chemical synthesis to unlock the biosynthetic potential contained in even complex uncharacterized BGCs.
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