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Although natural products are essential sources of small‐molecule antitumor drugs, some can exert substantial toxicities, limiting their clinical utility. Anthraquinone‐fused enediyne natural products are remarkably potent antitumor drug candidates, and uncialamycin and tiancimycin (TNM) A are under development as antibody‐drug conjugates. Herein, a novel drug delivery system is introduced for TNM A using anti‐human epidermal growth factor receptor 2 (HER2) immunoliposomes (ILs). Trastuzumab‐coated TNM A‐loaded ILs (HER2‐TNM A‐ILs) is engineered with an average particle size of 182.8 ± 2.1 nm and a zeta potential of 1.75 ± 0.12 mV. Compared with liposomes lacking trastuzumab, HER2‐TNM A‐ILs exhibited selective toxicity against HER2‐positive KPL‐4 and SKBR3 cells. Coumarin‐6, a fluorescent TNM A surrogate, is encapsulated within anti‐HER2 ILs; the resultant ILs have enhanced cellular uptake in KPL‐4 and SKBR3 cells when compared with control liposomes. Furthermore, ILs loaded with more Cy5.5 accumulated in KPL‐4 mouse tumors. A single HER2‐TNM A‐IL dose (0.02 mg kg−1) suppressed the growth of HER2‐positive KPL‐4 mouse tumors without apparent toxicity. This study not only provides a straightforward method for the effective delivery of TNM A against HER2‐positive breast tumors but also underscores the potential of IL‐based drug delivery systems when employing highly potent cytotoxins as payloads. [ABSTRACT FROM AUTHOR]

Covering: up to the end of July, 2021 Anthraquinone-fused enediynes (AFEs) are a subfamily of enediyne natural products. Dynemicin A (DYN A), the first member of the AFE family, was discovered more than thirty years ago. Subsequently, extensive studies have been reported on the mode of action and the interactions of AFEs with DNA using DYN A as a model. However, progress in the discovery, biosynthesis and clinical development of AFEs has been limited for a long time. In the past five years, four new AFEs have been discovered and significant progress has been made in the biosynthesis of AFEs, especially on the biogenesis of the anthraquinone moiety and their tailoring steps. Moreover, the streamlined total synthesis of AFEs and their analogues boosts the preparation of AFE-based linker-drugs, thus enabling the development of AFE-based antibody–drug conjugates (ADCs). This review summarizes the discovery, mechanism of action, biosynthesis, total synthesis and preclinical studies of AFEs. [ABSTRACT FROM AUTHOR]

Summary: Acyltransferase (AT)‐less type I polyketide synthases (PKSs) produce complex natural products due to the presence of many unique tailoring enzymes. The 3‐hydroxy‐3‐methylglutaryl coenzyme A synthases (HCSs) are responsible for β‐alkylation of the growing polyketide intermediates in AT‐less type I PKSs. In this study, we discovered a large group of HCSs, closely associated with the characterized and orphan AT‐less type I PKSs through in silico genome mining, sequence and genome neighbourhood network analyses. Using HCS‐based probes, the survey of 1207 in‐house strains and 18 soil samples from different geographic locations revealed the vast diversity of HCS‐containing AT‐less type I PKSs. The presence of HCSs in many AT‐less type I PKSs suggests their co‐evolutionary relationship. This study provides a new probe to study the abundance and diversity of AT‐less type I PKSs in the environment and microbial strain collections. Our study should inspire future efforts to discover new polyketide natural products from AT‐less type I PKSs. [ABSTRACT FROM AUTHOR]

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard., Chemistry and Chemical Biology

The enediyne natural products have been explored for their phenomenal cytotoxicity. The development of enediynes into anticancer drugs has been successfully achieved through the utilization of polymer- and antibody–drug conjugates (ADCs) as drug delivery systems. An increasing inventory of enediynes would benefit current application of ADCs in many oncology programs. Innovations in expanding the enediyne inventory should take advantage of the current knowledge of enediyne biosynthesis and post-genomics technologies. Bioinformatics analysis of microbial genomes reveals that enediynes are underexplored, in particular from Actinomycetales. This digest highlights the emerging opportunities to explore microbial genomics for the discovery of novel enediyne natural products. [ABSTRACT FROM AUTHOR]