Current Drug Targets (v.12, #11)
Editorial [Hot Topic: Natural Products in Chemical Biology (Guest Editor: Jurg Gertsch)] by Jurg Gertsch (1513-1514).
Secondary metabolism plays a major role in the evolution of organisms as they represent a source of highly diversifiedmolecular scaffolds able to interact with multiple protein targets [1, 2]. Such interactions may both serve as molecular clues todeter competitors, or alternatively facilitate symbiosis [3, 4]. Thus, natural products are building blocks to generate and respondto evolutionary pressure. In the past millenia, humankind has relied on natural products for the elaboration of medicines andpoisons [5, 6]. Indeed, some of the most influential molecules were discovered from medicinal and poisonous plants .Insights into molecular mechanisms and the elucidation of macromolecular structures in the last fifty years has led to a targetbasedapproach in the discovery and design of novel drug leads. Despite the opportunities offered by fully synthetic librariesand biologics, natural products continue to play important roles as lead compounds and unique probes to manipulate biologicalsystems.The still widely unexplored pools of secondary metabolites currently found in microorganisms, plants and animals indistinct ecological niches are highly dynamic and have most likely been selected for addressing a wide range of biologicalfunctions [8, 9]. This may be the reason why natural products have yielded a high number of molecules for drug development.The biosynthetic pathways leading to molecular diversity in microorganisms provide a new frontier for the rational generationof novel types of secondary metabolites. Moreover, a central aim of biological research is to elucidate the many roles ofmacromolecules in complex, dynamic living systems . As uncovered in this issue, basic research directed against differentorganisms is revealing unexpected insights into fundamental biological roles of natural products and how these could beexploited in drug discovery.The review articles included in this hot topic issue of Current Drug Targets summarize current examples of how naturalproduct diversity is being used in biological research and drug discovery, thus highlighting the natural products’ outstandingproperties and bioactivities from different perspectives. Overall, natural products are the prototype players in chemical biology......
Biodiversity and Chemodiversity: Future Perspectives in Bioprospecting by B.T. Ramesha, Jurg Gertsch, G. Ravikanth, V. Priti, K.N. Ganeshaiah, R. Uma Shaanker (1515-1530).
Biological diversity and its constituent chemical diversity have served as one of the richest sources ofbioprospecting leading to the discovery of some of the most important bioactive molecules for mankind. Despite thisexcellent record, in the recent past, however, bioprospecting of biological resources has met with little success; there hasbeen a perceptible decline in the discovery of novel bioactive compounds. Several arguments have been proposed toexplain the current poor success in bioprospecting. Among them, it has been argued that to bioprospect more biodiversitymay not necessarily be productive, considering that chemical and functional diversity might not scale with biologicaldiversity.In this paper, we offer a critique on the current perception of biodiversity and chemodiversity and ask to what extent it isrelevant in the context of bioprospecting. First, using simple models, we analyze the relation among biodiversity,chemodiversity and functional redundancies in chemical plans of plants and argue that the biological space for explorationmight still be wide open. Second, in the context of future bioprospecting, we argue that brute-force high throughputscreening approaches alone are insufficient and cost ineffective in realizing bioprospecting success. Therefore, intelligentor non-random approaches to bioprospecting need to be adopted. We review here few examples of such approaches andshow how these could be further developed and used in the future to accelerate the pace of discovery.
Exploring and Exploiting Biologically Relevant Chemical Space by Luc Eberhardt, Kamal Kumar, Herbert Waldmann (1531-1546).
Small bioactive molecules are pre-requisite for any discovery discipline. Being aware of the fact thatbioactivity is not randomly dispersed in the vast chemical space, chemists have been developing hypothesis that canprovide access to these islands of bioactivities. Natural products have always been a source of inspiration and theirstructural motifs provide biologically relevant starting points for library synthesis. In addition to that, Diversity OrientedSynthesis (DOS) and Biology Oriented Synthesis (BIOS) have emerged other tools to guide synthesis design and helpenrich compound collections in biological activities. Coherent developments in chem- and bioinformatic tools and inorganic synthesis methods targeting efficient synthesis of compound collections are required to identify interestingmolecules that can be employed as probes in chemical biology research and as drug candidates in medicinal chemistryinvestigations.
Discovery of Antibacterials and Other Bioactive Compounds from Microorganisms- Evaluating Methodologies for Discovery and Generation of Non-Ribosomal Peptide Antibiotics by K. Witting, R.D. Sussmuth (1547-1559).
After decades of neglect in industrial research the comeback of natural products is due since improvedscreening approaches are at disposal, yielding a multitude of new compounds from natural sources. Besides traditionalcompound libraries peptides are characterized by an enormous structural complexity, thus increasing the chance of findinga hit in a screening. Emphasizing antibacterial compounds structural complexity is a prerequisite for their success.This review focuses on the screening approaches employed for the discovery of mostly antibacterial, non-ribosomalpeptides derived from natural sources. Traditional screening methodologies as well as genetic approaches are discussed inthis context. Utilizing genetic engineering methods e.g., precursor-directed biosynthesis, mutasynthesis, combinatorialbiosynthesis, as well as chemoenzymatics to achieve greater structural diversity is thoroughly discussed and exemplifiedby recent discoveries.
Perspectives on Sesquiterpene Lactones in Inflammation and Cancer by Irmgard Merfort (1560-1573).
Sesquiterpene lactones are a large group of secondary plant metabolites mostly known from the Asteraceaefamily. They exert a broad variety of different biological activities. This review attempts to critically summarise theknowledge on the anti-inflammatory and cytotoxic activity of SLs, with a special focus on parthenolide and helenalin.Recent advances on their molecular modes of action, allergic potential and also QSAR studies with SLs are presented.Therapeutic areas are highlighted in which SLs may play a role in the future. Thus, SLs may possess therapeutic relevanceas single components for the local treatment of inflammation, such as rheumatoid complaints. In cancer therapy, SLs maybe favourable in dual therapy or in the inhibition of leukaemia cell growth. In each case, native SLs serve as leads thathave to be optimised in terms of their specificity, pharmacokinetics and absorption, distribution, metabolism and excretion(=ADME) properties. Finally, appropriate in vivo studies will decide whether SLs will become therapeutics or remaininteresting research compounds.
Controlling Protein Transport by Small Molecules by Karl Gademann (1574-1580).
Many proteins are transported from the nucleus to the cytoplasm by the exportin CRM1, which recognizescargo proteins through a leucine rich nuclear export signal (NES). This nuclear export process can be inhibited by severalsmall molecules, both natural products and fully synthetic compounds. The structural basis for the inhibition of nuclearexport by leptomycin (LMB) based on disruption of the protein/protein interaction between CRM1 and cargo proteins isdiscussed. The chemistry and inhibition of nucleocytoplasmic transport of leptomycin, anguinomycin and derivatives,goniothalamin, JBIR-02, valtrate, dihydrovaltrate, ACA, peumusolide A and several synthetic compounds are presented.Consequences for the design of nuclear export inhibitors are discussed, and the potential of these compounds as anticanceragents is evaluated.
Natural Product Inhibitors of the Ubiquitin-Proteasome Pathway by John S. Schneekloth, Craig M. Crews (1581-1594).
Natural products continue to be a source of inspiration for chemists and biologists alike. The search forbiologically active natural products has provided troves of information about biological processes, and natural productscontinue to be some of the most powerful and useful probes of biological processes available. Complex and unusualmolecular architectures provide the impetus for new reaction development and push the limits of known syntheticchemistry. In addition to serving as tools for basic research, natural products represent starting points for drug discoveryefforts in many cases.This review details the impressive chemical diversity present in the family of molecules that inhibit the proteasome andother aspects of the ubiquitin-proteasome pathway. To date, over 60 natural products that inhibit the ubiquitin-proteasomepathway have been identified. Although early work recognized inhibitors of the proteasome itself, more modern researchhas revealed that inhibition of many aspects of this critical pathway is possible. One powerful example of this is theinhibition of the interaction between p53 and MDM2 (an E3 ubiquitin ligase). Natural product proteasome inhibitors haveserved as powerful tools to unravel the intricacies of the ubiquitin-proteasome and related pathways. Several of thesenatural products have been developed into anticancer drug candidates, and one proteasome inhibitor has already beenapproved for the treatment of multiple myeloma. Despite the wealth of information available about naturally occurringproteasome inhibitors and related compounds, it is clear that exciting research about this class of molecules will continuewell into the future.
Identification of Novel Anti-inflammatory Agents from Ayurvedic Medicine for Prevention of Chronic Diseases: “Reverse Pharmacology” and “Bedside to Bench” Approach by Bharat B. Aggarwal, Sahdeo Prasad, Simone Reuter, Ramaswamy Kannappan, Vivek R. Yadav, Byoungduck Park, Ji Hye Kim, Subash C. Gupta, Kanokkarn Phromnoi, Chitra Sundaram, Seema Prasad, Madan M. Chaturvedi, Bokyung Sung (1595-1653).
Inflammation, although first characterized by Cornelius Celsus, a physician in first Century Rome, it wasRudolf Virchow, a German physician in nineteenth century who suggested a link between inflammation and cancer,cardiovascular diseases, diabetes, pulmonary diseases, neurological diseases and other chronic diseases. Extensiveresearch within last three decades has confirmed these observations and identified the molecular basis for most chronicdiseases and for the associated inflammation. The transcription factor, Nuclear Factor-kappaB (NF-κB) that controls over500 different gene products, has emerged as major mediator of inflammation. Thus agents that can inhibit NF-κB anddiminish chronic inflammation have potential to prevent or delay the onset of the chronic diseases and further even treatthem. In an attempt to identify novel anti-inflammatory agents which are safe and effective, in contrast to high throughputscreen, we have turned to “reverse pharmacology” or “bed to benchside” approach. We found that Ayurveda, a science oflong life, almost 6,000 years old, can serve as a “goldmine” for novel anti-inflammatory agents used for centuries to treatchronic diseases. The current review is an attempt to provide description of various Ayurvedic plants currently used fortreatment, their active chemical components, and the inflammatory pathways that they inhibit.
Chemodiversity in Freshwater and Terrestrial Cyanobacteria - A Source for Drug Discovery by George E. Chlipala, Shunyan Mo, Jimmy Orjala (1654-1673).
Cyanobacteria are considered a promising source for new pharmaceutical lead compounds and a large numberof chemically diverse and bioactive metabolites have been obtained from cyanobacteria over the last few decades. Thisreview highlights the structural diversity of natural products from freshwater and terrestrial cyanobacteria. The review isdivided into three areas: cytotoxic metabolites, protease inhibitors, and antimicrobial metabolites. The first sectiondiscusses the potent cytotoxins cryptophycin and tolytoxin. The second section covers protease inhibitors from freshwaterand terrestrial cyanobacteria and is divided in five subsections according to structural class: aeruginosins, cyanopeptolins,microviridins, anabaenopeptins, and microginins. Structure activity relationships are discussed within each proteaseinhibitor class. The third section, antimicrobial metabolites from freshwater and terrestrial cyanobacteria, is divided bychemical class in three subsections: alkaloids, peptides and terpenoids. These examples emphasize the structural diversityand drug development potential of natural products from freshwater and terrestrial cyanobacteria.
Modulation of GABAA Receptors by Natural Products and the Development of Novel Synthetic Ligands for the Benzodiazepine Binding Site by Jakob Nilsson, Olov Sterner (1674-1688).
Nature provides science and society with a virtually unlimited supply of structurally diverse and biologicallyactive molecules; the natural products. While some are directly useful in commercial applications, others are valuable forstudying and understanding biological phenomena at the molecular level. An example is the signaling of nerve cells,which has been explored in considerable detail using a number of bioactive natural products. This review concernsprimarily a part of the GABA inhibitory system of the central nervous system, the GABAA receptors, and natural productsthat have been reported to affect GABAA receptors in various ways. As the major inhibitory neurotransmittor, GABAplays a central role in the function of the central nervous system and modulates the activities of all neurons. Malfunctionsin the GABA-operated systems cause a number of severe mental disorders, which consequently, at least in theory, can betreated with drugs. The natural products discussed in this review, acting on the GABAA receptors, are divided into thethree main classes; terpenoids, polyacetylenic alcohols, and flavonoids. In addition, in a second part of the review, it isexemplified how knowledge about quantitative structure-activity relationships for a molecular target can be used to designnovel, potent and selective compounds targeting the benzodiazepine binding site of the GABAA receptors.
2-Aminoimidazole, Glycociamidine and 2-Thiohydantoin-Marine Alkaloids as Molecular Inspirations for the Development of Lead Structures by Ravi Kumar, Shahnawaz Khan, Prem M.S. Chauhan (1689-1708).
This review provides a detailed account on the biological activities of structurally diverse secondarymetabolites from marine sponges having 2-aminoimidazole, glycociamidine and/or 2-thiohydantoin ring functions. Thisreview will complement two previous short reviews which did however not address the potential of these natural productsfor drug discovery. We will discuss the naturally occurring alkaloids and give an account on their structure activityrelationships.