Dereplication: Racing to Speed up the Natural Products Discovery Process Cite This: DOI: 10.1039/C4np00134f Susana P
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NPR View Article Online REVIEW View Journal Dereplication: racing to speed up the natural products discovery process Cite this: DOI: 10.1039/c4np00134f Susana P. Gaudencioˆ *ab and Florbela Pereiraa Covering: 1993–2014 (July) To alleviate the dereplication holdup, which is a major bottleneck in natural products discovery, scientists have been conducting their research efforts to add tools to their “bag of tricks” aiming to achieve faster, more accurate and efficient ways to accelerate the pace of the drug discovery process. Consequently Received 21st October 2014 dereplication has become a hot topic presenting a huge publication boom since 2012, blending DOI: 10.1039/c4np00134f multidisciplinary fields in new ways that provide important conceptual and/or methodological advances, www.rsc.org/npr opening up pioneering research prospects in this field. 1 Introduction 1 Introduction 2 Reviews 3 Facts and statistics Nowadays, the presumably high productivity in terms of the 4 Dereplication trends and approaches number of novel bioactive compounds isolated has not yet led 5 High throughput screening (HTS) to a corresponding increase in the number of new drug candi- 6 Analytical technologies dates. Instead, aer more than two decades of combinatorial 6.1 Separation techniques chemistry research, a declining number of new chemical enti- 6.2 Detection methods ties (NCEs) in the drug development pipeline has been 6.3 Hyphenated techniques observed,1 Fig. 1. 7 Computational mass spectrometry tools for dereplication This phenomenon combined with the higher success rate of 7.1 Ligand-guided approach – small molecules drug discovery obtained from the marine world (1 in 3140 marine 7.2 Genome-guided approach natural products) compared with the industry average (1 in 5000– Published on 08 April 2015. Downloaded by RUTGERS STATE UNIVERSITY 08/04/2015 13:25:10. 8 X-ray crystallography 10 000 compounds) has led to the rekindled interest in natural 9 NMR products-like scaffolds.2 Natural products (NPs) sources are well 10 Computer assisted structure elucidation (CASE) known to produce chemical metabolites with unique features, 11 NPs databases highly complex structures and properties for human health care 12 The “omics” revolution and well-being, exhibiting a wide range of applications that have 12.1 Genomics inspired a number of industrial arenas. There is no doubt that NPs 12.2 Metabolomics are the most consistently successful source of drug leads, as can be 12.3 Proteomics seenfromFig.1.Theurgetoll the industrial pipeline and to 13 In silico dereplication discover novel lead-like compounds for drug discovery, which can 14 Combined techniques meet the societal challenge of the lack of suitable therapeutic 15 Conclusions and future prospects agents for a broad range of diseases, has never been greater. 16 Funding information Antibiotic resistance, for instance is a “ticking time bomb”,weare 17 References currently on “red alert”, having a poor drug repertoire, in which commonly treated infections are becoming lethal. One dominant tailback in NPs discovery is dereplication, i.e. the discard of known compounds. With the ultimate objective of speeding up and improving drug discovery program efficiency, researchers have aLAQV, REQUIMTE, Departamento de Qu´ımica, Faculdade de Ciˆencias e Tecnologia, been using multifaceted approaches, either merging different Universidade Nova de Lisboa, 2829-516 Caparica, Portugal. E-mail: s.gaudencio@ areas of knowledge or creating totally innovative ways to advance fct.unl.pt; Fax: +351 212948550; Tel: +351 212948300 this eld. Consequently, dereplication, which is the object of our bUCIBIO, REQUIMTE, Departamento de Ciˆencias da Vida, Faculdade de Ciˆencias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal review, has become a matter of great interest in recent years. The This journal is © The Royal Society of Chemistry 2015 Nat. Prod. Rep. View Article Online NPR Review Fig. 1 Comparison between dereplication outputs, NPs approved drugs and total NCEs approved drugs. (http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/DrugInnovation/ucm20025676.htm).1 importance of dereplication can be proven by the signicant reviews focusing on several and diverse NPs dereplication increase of publications covering this topic since 2012 (Fig. 1). aspects will be highlighted. A vast number of reviews describing Therefore,webelievethatthedevelopmentofmultidisciplinary the enhanced technological progress of hyphenated tools and dereplication processes, which will be highlighted in this review, combined dereplication strategies that have been pivotal to willcertainlyresultinanimpressive enhancement in the number accelerate the speed of novel NPs isolation process have been of NPs (or directly derived therefrom) and approved drugs in the reported.3–7 Others particularly debate the emerging advances imminent future. Our insight into this theme will cover the period in chromatography, mass spectrometry (MS) and NMR tech- from 1993 to 2014 (July). In this review we do not intend to give an nologies to overcome the challenges encountered in screening exhaustive description of the focused techniques and methodolo- NPs libraries, increasing the role of NPs in high-throughput gies. Instead we will refer to their use from the NPs dereplication screening (HTS) based drug discovery.8–11 The approaches used point of view, giving priority to signicant reported progress in this in biodiversity- and taxonomy-guided microbial NPs library area, emphasizing key developments that have shaped the eld, construction, combined with HTS and with Liquid Chroma- trends and describing future directions. tography-Mass Spectrometry (LC-MS) have been promoted as efficient dereplication processes.12 Furthermore, signicant advances in the eld of computational mass spectrometry for 2 Reviews NPs research, highlighting recently developed methods for the Over forty reviews on the “dereplication” topic have been detection and investigation of small molecules, namely Met- 13 reported, according to the information obtained from ISI Web Frag/MetFusion, ISIS, FingerID, and FT-BLAS, were reviewed. of Science™ and NPR archive. Hence, a selection of several The latest applications of Imaging Mass Spectrometry (IMS) Published on 08 April 2015. Downloaded by RUTGERS STATE UNIVERSITY 08/04/2015 13:25:10. Susana P. Gaudˆencio is Florbela Pereira is currently a currently a Researcher Chemist Researcher Chemoinformatics at at LAQV and UCIBIO LAQV REQUIMTE-Faculdade de REQUIMTE-Faculdade de Ciˆen- Ciˆencias e Tecnologia da Uni- cias e Tecnologia da Uni- versidade Nova de Lisboa, Por- versidade Nova de Lisboa, tugal. She holds degrees in Portugal. She holds degrees in chemistry – analytical chemistry technological organic chemistry (1991) and in natural products (M.S. 2001) and in organic (Ph.D. 1997) from the University chemistry (Ph.D. 2006), was a of Aveiro. She undertook post- postdoc at Scripps Institution of doctoral research on the devel- Oceanography (SIO), UC-San opment of pharmaceutical Diego (2007–2010). Susana’s products at the Instituto de early interests have crossed several disciplines including the Biologia Experimental e Tecnologica´ (IBET). During 2000–2005, chemistry and ecology of marine sponges, and the total synthesis of Florbela worked in industry as a synthetic chemist in organic staurosporine precursors. Presently she is the PI of several projects synthesis of agrochemical active substances, before returning to related to marine microbiology, marine natural products drug academia to join the chemoinformatics and marine natural discovery and chemical ecology, particularly targeting microor- products groups. Her main scientic interests include machine ganisms from the Macaronesia Atlantic ecoregion. learning and data mining techniques. Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2015 View Article Online Review NPR technologies, challenges, pitfalls and prospects for improve- and SciELO Citation, prior to July 8th of 2014, in a total of 340 ment and application to microbial NPs were reviewed.14 Existing publications (277 articles, 21 proceedings and 42 reviews). All and emerging technological advances referring to MS related to publications incorporating the dereplication subject were NPs dereplication have been extensively reviewed and analyzed. Prior to 1993 until 2011 there was a steady increase in described.15 Recent studies emphasized metabolomics-driven the number of publications/year rising from 3 in 1993 to 19 analysis, using modern mass spectrometry techniques, as a key during 2011, there was a notable increase in the number of approach for the discovery of NPs from microbial sources.16 reports since 2011 (approximately 89%), corresponding to 49 Chemotyping/metabolomics as part of screening, using direct and 50 publications in 2012 and 2013, respectively. Worldwide metabolite proling techniques such as direct injection MS or more than three-quarters of the publications (i.e. 205 out of 243, NMR have been reviewed, focusing on how it can be used for the corresponding to 84%), during the last ten years, are linked to discovery of novel compounds in combination with modern ten countries, namely USA, Denmark, Switzerland, Brazil, Ger- methods for dereplication, avoiding redundancy in the selec- many, China, Australia, Netherlands, Canada and England. tion of microorganism species.17 However, 170 publications (out of 243, corresponding to 70%) As far as NMR is concerned, in a recent review,18 technical are related with