Jason Micklefield of the University of Manchester, UK, looks at how natural products hit the targets other molecules cannot reach

Natural products are an exceptional resource. These secondary metabolites are produced principally by bacteria, fungi, plants and marine organisms. Unlike primary metabolites they are not essential for the normal growth or development of an organism; some function in chemical defence, protecting the producer against invasion or infestation by other organisms, whilst others act as chemical signals, allowing communication and facilitating reproduction in certain species. 

But the natural role of the majority of these compounds remains unknown. It is likely that many natural products function by binding with high affinity and selectivity to biological macromolecules including DNA, RNA and particularly proteins. Indeed, it has been suggested that these interactions have been selected for across the 3 billion years of biological evolution.

Natural products often have physiological effects that arise from their innate potential to bind to specific biological targets. These have been recognised for many years. For example, evidence dating back 4000 years refers to plant remedies for various illnesses and even Neanderthal man is suggested to have used medicinally active plants some 60 000 years ago.

Since then, many natural products have been isolated, from plants and other organisms, and shown to elicit potent physiological responses in humans. Not surprisingly, this has led the modern pharmaceutical companies to develop natural products as antibiotics, antifungal, anticancer and immunosuppressive agents as well as other medicines. But despite this, over the past decade, a number of major pharmaceutical companies have ceased to follow up natural products as leads, in favour of simpler synthetic compounds. Regardless of this trend, natural product research in academia and other sectors has advanced significantly during this period.

The advent of chemical genetics and powerful high-throughput screening methodologies, has revealed a large number of new cellular targets with which natural products interact.¹ In chemical genomics small molecules, including natural products, are screened with the long term aim of identifying ligands that can modulate the function of all gene products in a cell. As a result many new natural product targets have been discovered that would not be explored in traditional pharmaceutical drug discovery programmes.

Also, with advances in structural biology we have seen a prodigious increase in the number of structures of key cellular targets characterised, including the ribosome, nucleosome and fatty acid synthases. As the sites with which natural products interact have begun to be resolved in detail, the modes of action of many natural products have been established.¹

Notable advances have also been made in our understanding of natural product biosynthesis.² For example, improvements in DNA sequencing have allowed genes encoding biosynthetic pathways to be identified and exploited in so-called genome mining approaches. Many natural product producing organisms are difficult to cultivate in the laboratory and their biosynthetic gene clusters can often remain cryptic. To overcome this, metagenomics approaches, which use DNA recovered from environmental samples, and heterologous expression methods, which use DNA from several different species, have allowed the first glimpses of a vast array of unexplored natural products.

Also, developments in biosynthetic engineering have enabled scientists to reprogram the biosynthesis of several major classes of natural products, altering organisms to make new derivatives. Not only does this increase the number of product analogues for screening, but it also allows the physiochemical and biological properties of key lead compounds to be further optimised.

For more than 3 billion years nature has used natural products to modulate biomolecule function within the cell. Despite this, it has been chiefly only in the past few years, through advances in genomics, structural biology and related technologies, that we have begun to appreciate fully the immense and largely untapped resource that natural products provide.

Read Dixon, Wong, Geerlings and Micklefield's review 'Cellular targets of natural products in the latest issue of Natural Product Reports.