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Drug discovery and natural products: end of an era or an endless frontier?
Literature Information
| DOI | 10.1126/science.1168243 |
|---|---|
| PMID | 19589993 |
| Journal | Science (New York, N.Y.) |
| Impact Factor | 45.8 |
| JCR Quartile | Q1 |
| Publication Year | 2009 |
| Times Cited | 603 |
| Keywords | Drug discovery, Natural products, Biological resources, Synthetic biology, Metabolic engineering |
| Literature Type | Journal Article, Research Support, Non-U.S. Gov't, Review |
| ISSN | 0036-8075 |
| Pages | 161-5 |
| Issue | 325(5937) |
| Authors | Jesse W-H Li, John C Vederas |
TL;DR
The decline in pharmaceutical research on natural products over the past 15 years has coincided with reduced new drug approvals and the looming expiration of patents on key medications. However, advancements in "smart screening" methods, robotic separation, metabolic engineering, and synthetic biology, along with rapid genetic sequencing, present promising opportunities for the discovery of new pharmaceuticals derived from untapped biological resources.
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Drug discovery · Natural products · Biological resources · Synthetic biology · Metabolic engineering
Abstract
Historically, the majority of new drugs have been generated from natural products (secondary metabolites) and from compounds derived from natural products. During the past 15 years, pharmaceutical industry research into natural products has declined, in part because of an emphasis on high-throughput screening of synthetic libraries. Currently there is substantial decline in new drug approvals and impending loss of patent protection for important medicines. However, untapped biological resources, "smart screening" methods, robotic separation with structural analysis, metabolic engineering, and synthetic biology offer exciting technologies for new natural product drug discovery. Advances in rapid genetic sequencing, coupled with manipulation of biosynthetic pathways, may provide a vast resource for the future discovery of pharmaceutical agents.
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Primary Questions Addressed
- What specific technologies in "smart screening" are currently being developed to enhance the discovery of natural products?
- How do advances in rapid genetic sequencing influence the traditional methods of drug discovery from natural products?
- What role does metabolic engineering play in optimizing the production of secondary metabolites for pharmaceutical use?
- Can you discuss the potential of synthetic biology in creating novel compounds that could rival traditional natural products in drug discovery?
- What are the implications of declining new drug approvals for the future research and investment in natural product-derived pharmaceuticals?
Key Findings
Key Insights:
Research Background and Objective: The historical reliance on natural products (secondary metabolites) as a primary source for new drug development has been well-documented, with many successful pharmaceuticals derived from these compounds. However, over the last 15 years, there has been a noticeable decline in the pharmaceutical industry's focus on natural products. This shift is attributed to the prioritization of high-throughput screening techniques applied to synthetic compound libraries. The objective of this research is to evaluate the current state of natural product drug discovery and assess whether it marks the end of an era or the beginning of a new frontier in pharmaceutical research.
Main Methods and Findings: The research highlights the significant decline in new drug approvals and the impending expiration of patents for existing medications, which raises concerns about the future of pharmaceutical innovation. Despite this decline, the study identifies numerous advanced technologies that could revitalize the exploration of natural products. These include "smart screening" methods that enhance the efficiency of compound identification, robotic separation techniques combined with structural analysis for accurate compound characterization, metabolic engineering for modifying biosynthetic pathways, and synthetic biology approaches that could facilitate the creation of novel bioactive compounds. Advances in rapid genetic sequencing are also emphasized as a transformative tool, enabling researchers to unlock and manipulate the genetic blueprints of natural product biosynthesis.
Core Conclusions: The findings suggest that while the traditional approach to natural product drug discovery has faced challenges, there is significant potential for reinvigorating this field through innovative technologies. The authors conclude that the decline in interest in natural products may be a temporary setback rather than a definitive end, as new methodologies can lead to the discovery of previously untapped biological resources.
Research Significance and Impact: This research holds profound implications for the future of drug discovery. By advocating for a renewed focus on natural products, coupled with cutting-edge technologies, it encourages the pharmaceutical industry to reevaluate its strategies and explore the potential of natural compounds as sources of new therapeutics. The integration of modern techniques with traditional natural product research could lead to breakthroughs in drug development, addressing the current stagnation in new drug approvals and ensuring a sustainable pipeline of innovative medicines. Furthermore, this approach could enhance the understanding of biodiversity and promote the conservation of biological resources essential for pharmaceutical advancements.
Literatures Citing This Work
- Beyond directed evolution: Darwinian selection as a tool for synthetic biology. - Manuel Porcar - Systems and synthetic biology (2010)
- Development of a high-throughput cell-based reporter assay to identify stabilizers of tumor suppressor Pdcd4. - Johanna S Blees;Tobias Schmid;Cheryl L Thomas;Alyson R Baker;Lauren Benson;Jason R Evans;Ekaterina I Goncharova;Nancy H Colburn;James B McMahon;Curtis J Henrich - Journal of biomolecular screening (2010)
- Preparation and biological evaluation of novel leucomycin analogs derived from nitroso Diels-Alder reactions. - Baiyuan Yang;Tina Zöllner;Peter Gebhardt;Ute Möllmann;Marvin J Miller - Organic & biomolecular chemistry (2010)
- Natural products version 2.0: connecting genes to molecules. - Christopher T Walsh;Michael A Fischbach - Journal of the American Chemical Society (2010)
- Capturing bacterial metabolic exchange using thin film desorption electrospray ionization-imaging mass spectrometry. - Jeramie Watrous;Nathan Hendricks;Michael Meehan;Pieter C Dorrestein - Analytical chemistry (2010)
- Sequence-based analysis of secondary-metabolite biosynthesis in marine actinobacteria. - Erin A Gontang;Susana P Gaudêncio;William Fenical;Paul R Jensen - Applied and environmental microbiology (2010)
- Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds. - Rui Zhang;Li Chen;Sarn Jiralerspong;Ann Snowden;Steven Steinberg;Nancy Braverman - Proceedings of the National Academy of Sciences of the United States of America (2010)
- The continuing search for antitumor agents from higher plants. - Li Pan;Heebyung Chai;A Douglas Kinghorn - Phytochemistry letters (2010)
- Virtual screening: an endless staircase? - Gisbert Schneider - Nature reviews. Drug discovery (2010)
- Potential of plant-derived natural products in the treatment of leukemia and lymphoma. - David M Lucas;Patrick C Still;Lynette Bueno Pérez;Michael R Grever;A Douglas Kinghorn - Current drug targets (2010)
... (593 more literatures)
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