Why should we be interested in studying natural products?
Natural products remain the best sources of drugs and drug leads
Natural products remain the best sources of drugs and drug leads, and this remains true today despite the fact that many pharmaceutical companies have de-emphasized natural product research in favour of HTP screening of combination libraries over the past two decades. From 1940 to the present, 131 (74.8%) of the 175 small molecule cancer drugs are based on natural or inspired products, of which 85 (48.6%) are natural or derived products. From 1981 to the present, 79 (80%) of the 99 small molecule cancer drugs are natural products, of which 53 (53%) are natural products or derived from them. Of the 20 small new chemical entities (NCEs) approved in 2010, half are natural products.Natural products have an enormous structural and chemical diversity that is unmatched by any synthetic library. About 40% of the chemical scaffolding found in natural products is missing from the current medicinal chemistry inventory. According to various chemical properties, combinatorial compounds occupy a much smaller surface area in the molecular space than natural products. Although combinatorial compounds occupy a well-defined area, natural products and drugs occupy all this space and additional volumes. More importantly, natural products are optimized for evolution as drug molecules. This is obvious when you realize that natural products and drugs occupy roughly the same molecular space.
Natural products represent the richest source of new molecular scaffolding and chemicals. No one can predict in advance how a small molecule will interact with the myriad of targets that we now know are the drivers of fundamental biological processes. The history of natural product discovery is full of remarkable stories about how the discovery of a natural product has profoundly influenced the progress of biology and therapy. For example, the impact of Taxol on tubulin polymerization, the correlation with the antitumor action or binding of rapamycin to mTOR and the ramifications of mTOR inhibitors could never be predicted a priori. The discovery of new natural products promises significant advances not only in chemistry, but also in biochemistry and medicine.
Natural products are significantly under-represented in today's small molecule banks.
Despite the great success of natural products in the history of drug discovery, natural products are significantly under-represented in today's small molecule banks. The challenges of natural products in drug discovery and development include (i) extremely low yields, (ii) limited supply, (iii) complex structures that pose enormous difficulties for structural modifications, and (iv) complex structures that prevent practical synthesis. These difficulties have led the pharmaceutical industry to adopt new technologies over the past two decades, including combinatorial chemistry, to the detriment of interest in the discovery of natural products.
Natural microbial products as the preferred sources of new drugs and new drug leads
Natural microbial products have several intrinsic properties that facilitate their consideration in drug discovery and development. Natural microbial products can be produced by large-scale fermentation. Microorganisms can be designed to overproduce the desired natural products and thus solve the problem of overcrowding. Analogues of natural microbial products can be produced by metabolic pathway engineering, providing a targeted library for studies on structure-activity-relationship relationships. The vast untapped ecological biodiversity of microbes holds great promise for the discovery of new natural products, thus improving the chances of finding new drug leads.
Natural products represent the richest source of new molecular scaffolding and chemicals. No one can predict in advance how a small molecule will interact with the myriad of targets that we now know are the drivers of fundamental biological processes. The history of natural product discovery is full of remarkable stories about how the discovery of a natural product has profoundly influenced the progress of biology and therapy. For example, the impact of Taxol on tubulin polymerization, the correlation with the antitumor action or binding of rapamycin to mTOR and the ramifications of mTOR inhibitors could never be predicted a priori. The discovery of new natural products promises significant advances not only in chemistry, but also in biochemistry and medicine.
Natural products are significantly under-represented in today's small molecule banks.
Despite the great success of natural products in the history of drug discovery, natural products are significantly under-represented in today's small molecule banks. The challenges of natural products in drug discovery and development include (i) extremely low yields, (ii) limited supply, (iii) complex structures that pose enormous difficulties for structural modifications, and (iv) complex structures that prevent practical synthesis. These difficulties have led the pharmaceutical industry to adopt new technologies over the past two decades, including combinatorial chemistry, to the detriment of interest in the discovery of natural products.
Natural microbial products as the preferred sources of new drugs and new drug leads
Natural microbial products have several intrinsic properties that facilitate their consideration in drug discovery and development. Natural microbial products can be produced by large-scale fermentation. Microorganisms can be designed to overproduce the desired natural products and thus solve the problem of overcrowding. Analogues of natural microbial products can be produced by metabolic pathway engineering, providing a targeted library for studies on structure-activity-relationship relationships. The vast untapped ecological biodiversity of microbes holds great promise for the discovery of new natural products, thus improving the chances of finding new drug leads.
The exponential growth in cloning and characterization of natural product biosynthesis machines from microbes over the past two decades has revealed unprecedented molecular knowledge about natural product biosynthesis, including the observation that natural product biosynthesis genes are grouped in the microbial genome and that variations in a few common biosynthetic machines may explain the high structural diversity observed for natural products. These results have fundamentally changed the landscape of natural products research by allowing the revision of known structures of natural products, the prediction of new compounds yet to be isolated on the basis of genetic sequences and the systematic generation of "unnatural" natural products by manipulating the genes governing their biosynthesis (also called combinatorial biosynthesis).
Sequencing the entire genome has revealed many more groups of biosynthetic genes than actual metabolites currently known for a given organism, suggesting that the biosynthetic potential of natural products in microorganisms is largely under-explored by traditional methods of natural product discovery. Among Streptomyces whose genomes have been sequenced, each has the potential to produce up to 30 natural products on average, and this optimism has already translated into the discovery of new natural products by optimizing the fermentation of strains that were not previously known as natural product producers.
It is estimated that only 1% of the microbial community is cultivated in the laboratory, which means that the huge biodiversity of microbial natural products remains underestimated. The emergence of new methods of cultivation, culturally-independent methods of gene cluster expression in heterologous host models, as well as continued efforts and innovative approaches to the collection, identification and classification of new strains of microbes have opened up access to these previously inaccessible natural resources of products.
The future of discovery and development of microbial natural medicines remains bright. i) Advances in DNA sequencing will significantly contribute to genome sequencing and genomics-based natural product discovery. (ii) Advances in DNA synthesis and synthetic biology will greatly contribute to the reconstruction of the natural pathway of natural products, their design and expression in models or industrial centres for the production of natural products. (iii) Advances in PTS will further enhance the rapid selection of natural product libraries for increasing biological applications. (iv) Advances in isolated technologies, analytical techniques, automated robotics and database management will contribute significantly to the establishment of a natural products library. (v) Environmental challenges will continue to support the discovery and development of biologically based drugs, i.e. fermentation, metabolic pathway engineering and the use of renewable resources.
