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Why Natural Products?

Why 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 deemphasized natural products research in favor of HTP screening of combinatorial libraries during the past 2 decades.  From 1940s to date, 131 (74.8%) out of 175 small molecule anticancer drugs are natural product-based/inspired, with 85 (48.6%) being either natural products or derived therefrom.  From 1981 to date, 79 (80%) out of 99 small molecule anticancer drugs are natural product-based/inspired, with 53 (53%) being either natural products or derived therefrom.  Among the 20 approved small molecule New Chemical Entities (NCEs) in 2010, a half of them are natural products.

Natural products possess enormous structural and chemical diversity that is unsurpassed by any synthetic libraries.  About 40% of the chemical scaffolds found in natural products are absent in today’s medicinal chemistry repertoire.  Based on various chemical properties, combinatorial compounds occupy a much smaller area in molecular space than natural products.  Although combinatorial compounds occupy a well-defined area, natural products and drugs occupy all of this space as well as additional volumes.  Most importantly, natural products are evolutionarily optimized as drug-like molecules. This is evident upon realization that natural products and drugs occupy approximately the same molecular space.

Natural products represent the richest source of novel molecular scaffolds and chemistry. No one can predict, in advance, the details of how a small molecule will interact with the myriad of targets that we now know drive fundamental biological processes. The history of natural product discovery is full of remarkable stories of how the discovery of a natural product profoundly impacted advances in biology and therapy.  For instance, Taxol's impact on tubulin polymerization, and correlation to antitumor action or rapamycin's binding 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, biochemistry and medicine.

Natural products are significantly underrepresented in current small molecule libraries

In spite of the great success of natural products in the history of drug discovery, natural products are significantly underrepresented in current small molecule libraries.  Challenges of natural products in drug discovery and development include (i) extremely low yields, (ii) limited supply, (iii) complex structures posing enormous difficulty for structural modifications, and (iv) complex structures precluding practical synthesis.  These difficulties lead to the pharmaceutical industry to embrace new technologies in the past two decades, particularly combinatorial chemistry, at the detriment to interest in natural product discovery.

Microbial natural products as preferred sources of new drugs and drug leads

Microbial natural products have several intrinsic properties favoring their consideration in drug discovery and development.  Microbial natural products can be produced by large-scale fermentation.  Microorganisms can be engineered to overproduce the desired natural products hence to solving the supply bottleneck.  Microbial natural product analogues can be produced by metabolic pathway engineering, thereby providing a focused library for structure-activity-relationship studies.  The vast, untapped, ecological biodiversity of microbes holds great promise for the discovery of novel natural products, thereby improving the odds of finding novel drug leads.

The exponential growth in cloning and characterization of natural product biosynthetic machinery from microbes in the last two decades has unveiled unprecedented molecular insights into natural product biosynthesis, including the observation that genes for natural product biosynthesis are clustered in the microbial genome and that variations of a few common biosynthetic machineries can account for vast structural diversity observed for natural products. These findings have fundamentally changed the landscape of natural product research by enabling the revision of known natural product structures, the prediction of yet-to-be isolated novel compounds on the basis of gene sequences, and the systematic generation of “unnatural” natural products by manipulating genes governing their biosynthesis (also known as combinatorial biosynthesis).

Whole genome sequencing has revealed far more biosynthetic gene clusters than actual metabolites currently known for a given organism, suggesting that the biosynthetic potential for natural products in microorganisms is greatly under-explored by traditional natural product discovery methods. Among the Streptomyces whose genomes have been sequenced, every one of them 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 fermentation optimization from strains that otherwise were not previously known as natural product producers.

Only 1% of the microbial community has been estimated to be cultivated in the lab, implying that the vast biodiversity of microbial natural products remains underappreciated. Emerging new cultivating techniques, culture-independent methods by expressing gene clusters in model heterologous hosts, and diligent effort and innovative approaches in novel microbial strain collection, identification, and classification have started to permit access to these previously inaccessible natural product resources.

The future of microbial natural product drug discovery and development remains bright.  (i) Advances in DNA sequencing will greatly facilitate genome sequencing and genomics-based natural products discovery.  (ii) Advances in DNA synthesis and synthetic biology will greatly facilitate natural product pathway reconstruction, engineering, and expression in model or industrial hosts for natural product production.  (iii) Advances in HTS will further enable rapid screening of natural product libraries for an ever broader range of biological application.  (iv) Advances in isolation technologies, analytic methods, automatic robotics, and database management will greatly facilitate natural products library construction.  (v) Environmental concerns will further favor bio-based natural products drug discovery and development processes, i.e., fermentation, metabolic pathway engineering, and renewable resources.