Abstract
Bioorthogonal chemistry has recently emerged to be one of the most powerful tools in drug discovery and chemical biology. The exploration of it has successfully advanced the field of natural product research. In this Perspective, we survey current strategies for the installation of chemical handles into the molecular scaffolds of several major classes of natural products, including polyketides (PKs), non-ribosomal peptides (NRPs), and their hybrids. By tagging these natural products with chemical handles and coupling them with subsequent bioorthogonal reactions, researchers have visualized and studied the mode of action of natural products, as well as synthesized derivatives with better pharmaceutical properties. We conclude this Perspective by considering two questions: is there a general way to synthesize tagged PKs/NRPs? Does natural product labeling have a broader impact in the field of natural product research beyond current known applications?
Highlights
Nature’s small molecules derived from microbes, plants, and animals have played an enormous role in the history of medicinal and pharmaceutical chemistry
In the past two decades, more than one third of small molecule-based drugs approved by the US Food and Drug Administration (FDA) were natural products or their derivatives (Newman and Cragg, 2012)
It has been estimated that most major classes of antibiotics and over 70% of anti-cancer small molecule treatments are natural products, their derivatives or mimics (Newman and Cragg, 2012)
Summary
Nature’s small molecules derived from microbes, plants, and animals have played an enormous role in the history of medicinal and pharmaceutical chemistry. The strategy of extender unit engineering, based on a promiscuous AT domain that is native or achieved through site-directed mutagenesis, has led to the introduction of a clickable functionality into PKs and PK-NRP hybrids.
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