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Editorial Cite This: ACS Omega 2017, 2, 8794−8795
Natural Products Chemistry: What’s the Next Step?
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insights for the chemistry of natural products, with the capability to generate chemical diversity by using genome mining, mutasynthesis, combinatorial biosynthesis, metagenomics, and synthetic biology. Natural products can be used for many other purposes, such as in agriculture, in cosmetics, as dyes, as paints, as inks, etc. In addition, they are involved in ecological processes that include different organisms. Sometime ago, Schreiber, a renowned chemist from Harvard University, in his paper “Small molecules: The Missing Link in the Central Dogma” stated “small molecules have critical roles at all levels of biological complexities and yet remain orphans of the central dogma. Chemical biologists, working with small molecules, expand our understanding of these central elements of life”.3 Even though the search for new drugs from plants and other organisms is still exciting and attractive, chemistry has played a key role in the explanation of biological and biochemical observations, opening a number of opportunities in the area. Each single organism (plant, marine or terrestrial animals, microorganism, algae, among others) interacts with the ecosystem by different strategies, including chemical signals and/or chemical defenses. In this sense, secondary metabolites can be understood as words of an ecological and evolutionary language that governs the synchronization and modulation of metabolic pathways, organismic and biogeographic.4 Also, the natural products can have unknown physiological functions that must be deeply understood in the future.5 Using a simple generalization, we can suggest that natural products are chemical phenotypes of an organism opening new challenges for researchers. Once the classical bioassay-guided isolation methods showed initial analytical limitations such as time-consuming isolations, a requirement of large sample amounts; new approaches were required and have gradually converted the focus to fast analysis applying new technological advancements. These have evolved by combining well-known spectroscopic and spectrometry strategies, giving support to metadata analysis. In the last ten years, the capacity to inventory the chemistry of biological systems, using new analytical tools, particularly the linkage of various mass spectrometric techniques with computerized and statistical analyses, has been revolutionary. These were a result of joint effort between natural products chemists, analytical chemists, chemical biologists, and computational chemists, looking to understand the chemistry from the biology viewpoint.5 But what is the next step? The Biology perspective, i.e., those strategies usually defined as “omics protocols”, may allow a more holistic view of biological chemical interactions from natural products to large molecules such as DNA and proteins. In the future, the great amount of data, which will need to be analyzed by powerful informatics tools, will open the perspective to increase the number of combined databases and integrating all omic fields (genomic, transcriptomic, proteomic, and metabolomics).6 With this macroperspective,
lants and other living organisms have long been used as sources for different useful human products. Traditional medicines have always been a source for the cure of many diseases since antiquity. However, their rational use was possible only after the initial understanding of what were or were not the “proven biological activities” of the compounds present in plants and other natural product sources such as microbes and later marine invertebrates. These molecules are normally known as “secondary metabolites” meaning that they are not part of the regular metabolism of the organism that is required to maintain life but that they have other, usually not known properties. Then the search for new bioactive compounds (secondary metabolites) was developed, and as a consequence, a number of new molecules with different spectra of activities were found.1 This approach generated wonderful examples that can illustrate how materials derived from plants and microbes became medicines. Recently, in 2015, the Nobel Prize in Physiology or Medicine was divided into two, with half going to William C. Campbell and Satoshi O̅ mura “for their discoveries concerning a novel therapy against infections caused by roundworm parasites” and the other half to You-you Tu “for her discoveries concerning a novel therapy against Malaria”. Even though half of the prize refers to products from microorganisms, the molecules are also known as natural products. The discovery by You-you Tu is a typical example of how the traditional medicines can be the source of products of plant origin that can be transformed into drugs. Recently, Pye and co-workers provided insight for future discovery of bioactive natural products. Quantitative examination applying a data set of all published microbial and marine-derived natural products suggests a potential for discovery that is truly new, but significant innovation will be required to successfully find novel bioactive compounds.2 Numerous examples of bioactive natural products are known; however, their discoveries have always been associated with the development of new analytical techniques for both isolation and purification and for structural elucidation. Sometimes the isolation process is tedious and time consuming, and frequently, the most used approach known as bioguided isolation leads to the bioactive compound; however, in some cases, all the efforts result in a known compound or a new series of compounds with high toxicity. Usually, the natural products as found in living organisms may not be used directly as a drug, but their chemical “skeleton” becomes the inspiration for the development of structurally modified compounds with superior biological properties. This is often referred to as being “more drug-like” than the initial compound. Plants continue to be a rich source of interesting compounds; however, in the past decades there has been a change leading to the study other organisms, and certainly, microbes have caught the attention of scientists. Just to remember one example, the discovery of penicillin can be cited as one of the most remarkable findings on the area of natural products. The study of microorganisms and now their genomes has brought new © 2017 American Chemical Society
Published: December 8, 2017 8794
DOI: 10.1021/acsomega.7b01671 ACS Omega 2017, 2, 8794−8795
ACS Omega
Editorial
(8) Pickens, L. B.; Tang, Y.; Chooi, Y. H. Metabolic Engineering for the Production of Natural Products. Annu. Rev. Chem. Biomol. Eng. 2011, 2, 211−236.
we believe that in due course it will be possible to annotate the biological function for natural products, and considering what the late Prof. Otto Richard Gottlieb, a renowned Brazilian natural product chemist, once said, “humanity must understand the working of nature before using it for any purpose”. There is no doubt that by using modern approaches natural products chemists will continue, contributing to the discovery of new medicines, but there will also be an enormous impact from the metabolomics strategies designed to identify candidates that may modulate an ecological interaction, physiological functions, or pharmacological effects. In this way, there are enormous perspectives for young natural products researchers to work with omics strategies, looking for a global chemical analysis of biology. The new natural products scientists must be involved with the state of the art on computational tools and opening new areas of research including renewing the fundamental search of new biological activity molecules.7 The use of metabolic engineering has opened up a window to the use of synthetic biology, system biology, and metabolic modeling as tools to facilitate the access to the construction of known and new pathways in production of new products of high aggregated value.8 The elucidation of biosynthetic pathways and gene heterologous expression has become possible to use synthetic biology for the production of many interesting compounds. These sets of postgenome methods and approaches have opened up new horizons for young scientists in research of how natural products can assist human well-being and other ecological perspectives.
Norberto P. Lopes Paulo Cezar Vieira
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NPPNS, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
AUTHOR INFORMATION
ORCID
Norberto P. Lopes: 0000-0002-8159-3658 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629−661. (2) Pye, C. R.; Bertin, M. J.; Lokey, R. S.; Gerwick, W. H.; Linington, R. G. Retrospective analysis of natural products provides insights for future discovery trends. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 5601− 5606. (3) Schreiber, S. L. Small molecules: the missing link in the central dogma. Nat. Chem. Biol. 2005, 1, 64−66. ́ (4) Gottlieb, O. R.; Borin, M. R. M. B. Quimica-Biologia Quantitativa: um novo paradigma? Quim. Nova 2012, 35, 2105−2114. (5) Aksenov, A. A.; Silva, R.; Knight, R.; Lopes, N. P.; Dorrestein, P. C. Global chemical analysis of biology by mass spectrometry. Nat. Rev. Chem. 2017, 1, 0054. (6) Brunetti, A. E.; Carnevale Neto, F.; Vera, M. C.; Taboada, C.; Pavarini, D. P.; Bauermeister, A.; Lopes, N. P. An integrative omics perspective for the analysis of chemical signals in ecological interactions. Chem. Soc. Rev. 2017, DOI: 10.1039/C7CS00368D. (7) Paddon, C. J.; Keasling, J. D. Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat. Rev. Microbiol. 2014, 12, 355−367. 8795
DOI: 10.1021/acsomega.7b01671 ACS Omega 2017, 2, 8794−8795
