In the 10 July issue of Science, Jesse W.-H. Li and John C. Vederas of the University of Alberta reviewed the current state of natural products-based drug discovery and development, in a report entitled “Drug Discovery and Natural Products: End of an Era or an Endless Frontier?”
As of 1990, some 80% of marketed drugs were either natural products or analogues based on natural products. Two of the major families of natural products that have been of special interest to drug discovery researchers are the polyketides and the terpenoids. Examples of marketed polyketide drugs include the cancer drug doxorubicin, the antibiotic erythromycin, statins including lovastatin (Merck’s Mevocor) and derivatives such as simvastatin (Merck’s Zocor) and atorvastatin (Pfizer’s Lipitor), and the immunosuppressive drug rapamycin. Examples of marketed terpenoid drugs include paclitaxel (Bristol-Myers Squibb’s Taxol) and the cancer drugs vinblastine and vincristine.
During the 1990s and continuing to the present day, small-molecule drug discovery changed to emphasize libraries of synthetic organic compounds, for use in high-throughput screening (HTS). Many companies abandoned the field of natural products altogether. This was driven by pharmaceutical companies’ pursuit of blockbuster drugs, in order to produce the growth in revenues demanded by the companies’ shareholders.
As the fruits of genomics entered the pharmaceutical arena, HTS of synthetic compound libraries against genomics-derived targets became the governing paradigm of small-molecule drug discovery. Nevertheless, natural products and natural product derivatives still accounted for around 50% of newly approved drugs between 2005 and 2007. Over 100 natural products and natural product derivatives are now in clinical studies.
In the 1990s and 2000s, drug discovery researchers emphasized synthetic compounds over natural products because they are easy to synthesize, and are more amenable to use in HTS. They allow researchers to examine large numbers of compounds in a short amount of time. In contrast, natural products have complex structures, are often difficult to synthesize, may be present as small amounts of active compound in complex mixtures in their natural sources, and present a number of other difficulties. Nevertheless, hit rates with synthetic compound libraries are very low, less than 0.001%. For polyketide natural products, for example, hit rates have been about 0.3%.
Given the low output of marketed drugs (let alone blockbusters) emerging from the synthetic compound library-HTS-large scale genomics paradigm, drug discovery researchers may be drawn to look for alternatives that might give higher rates of productivity. We have spoken of biology-driven drug discovery as an alternative to large-scale genomics-driven drug discovery in earlier posts. This deals with the target discovery and validation side of drug discovery. Researchers may also want to look at the chemistry side of small-molecule drug discovery.
The authors of this review suggest that they take a new look at natural products. In their report, they review new technologies for gaining access to, screening, and synthesizing novel natural products and natural product derivatives. There are also a vast number of organisms that are yet to be explored for natural products with potential pharmaceutical activity. The authors of this review therefore believe that the field of natural product medicines may well experience a revival in the near future. The low productivity of the current paradigm of drug discovery may provide an additional impetus for researchers and companies to return to natural products as a source of new small-molecule drugs.
Among the technologies that the authors discuss is an application of synthetic biology known as metabolic engineering. This involves reengineering of natural metabolic pathways in microorganisms to produce useful pharmaceutical products, including difficult-to-synthesize natural products and novel natural product derivatives. Our report on synthetic biology, including metabolic engineering to produce terpenoid and polyketide natural products, was published by Decision Resources in 2007.
An example of a biotech company that had been commercializing the fruits of metabolic engineering is Biotica Technology (Cambridge, U.K.). Biotica had been using metabolic engineering to discover and develop polyketide natural product derivatives for treatment of such diseases as cancer, hepatitis C, asthma, and inflammation. (As of March 2013, NeuroVive (Lund, Sweden) acquired a portfolio of polyketide cyclophilin inhibitors from Biotica, which has gone out of business as of January 2013.)