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1.
Chimia (Aarau) ; 75(7): 620-633, 2021 Aug 25.
Article in English | MEDLINE | ID: mdl-34523403

ABSTRACT

Natural Products (NPs) are molecular' special equipment ' that impart survival benefits on their producers in nature. Due to their evolved functions to modulate biology these privileged metabolites are substantially represented in the drug market and are continuing to contribute to the discovery of innovative medicines such as the recently approved semi-synthetic derivative of the bacterial alkaloid staurosporin in oncology indications. The innovation of low molecular weight compounds in modern drug discovery is built on rapid progress in chemical, molecular biological, pharmacological and data sciences, which together provide a rich understanding of disease-driving molecular interactions and how to modulate them. NPs investigated in these pharmaceutical research areas create new perspectives on their chemical and biological features and thereby new chances to advance medical research. New methods in analytical chemistry linked with searchable NP-databases solved the issue of reisolation and enabled targeted and efficient access to novel molecules from nature. Cheminformatics delivers high resolution descriptions of NPs and explores the substructures that systematically map NP-chemical space by sp³-enriched fragments. Whole genome sequencing has revealed the existence of collocated gene clusters that form larger functional entities together with proximate resistance factors thus avoiding self-inhibition of the encoded metabolites. The analysis of bacterial and fungal genes provides tantalizing glimpses of new compound-target pairs of therapeutic value. Furthermore, a dedicated investigation of structurally unique, selectively active NPs in chemical biology demonstrates their extraordinary power as shuttles between new biological target spaces of pharmaceutical relevance.


Subject(s)
Biological Products , Databases, Factual , Drug Discovery , Drug Industry
2.
Mol Inform ; 39(11): e2000017, 2020 11.
Article in English | MEDLINE | ID: mdl-32203642

ABSTRACT

Natural products (NPs) have evolved over a very long natural selection process to form optimal interactions with biologically relevant macromolecules. NPs are therefore a very useful source of inspiration for the design of new drugs. In the present study we report the results of a cheminformatics analysis of a large database of NP structures focusing on their scaffolds. First, general differences between NP scaffolds and scaffolds from synthetic molecules are discussed, followed by a comparison of the properties of scaffolds produced by different types of organisms. Scaffolds produced by plants are the most complex and those produced by bacteria differ in many structural features from scaffolds produced by other organisms. The results presented here may be used as a guidance in selection of scaffolds for the design of novel NP-like bioactive structures or NP-inspired libraries.


Subject(s)
Bacteria/chemistry , Biological Products/analysis , Cheminformatics , Fungi/chemistry , Plants/chemistry , Animals
3.
J Nat Prod ; 82(5): 1258-1263, 2019 05 24.
Article in English | MEDLINE | ID: mdl-30933507

ABSTRACT

The two most striking features that discriminate natural products from synthetic molecules are their characteristic scaffolds and unique functional groups (FGs). In this study we systematically investigate the distribution of FGs in natural products from a cheminformatics perspective by comparing FG frequencies in natural products with those found in average synthetic molecules. We thereby aim for the identification of FGs that are characteristic for molecules produced by living organisms. In our analysis we also include information about the natural origins of the structures investigated, allowing us to link the occurrence of specific FGs to the individual producing species. Our findings have the potential for being applied in a medicinal chemistry context concerning the synthesis of natural product-like libraries and natural product-inspired fragment collections. The results may be used also to support compound derivatization strategies and the design of "non-natural" natural products.


Subject(s)
Biological Products/chemistry , Cheminformatics , Combinatorial Chemistry Techniques , Computational Biology , Molecular Structure , Structure-Activity Relationship
4.
J Biol Chem ; 294(10): 3359-3366, 2019 03 08.
Article in English | MEDLINE | ID: mdl-30647128

ABSTRACT

Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor affecting both host metabolism and immune responses, but its physiological roles remain unclear. We conducted a screen for microbiome metabolites that would function as inflammasome activators and herein report the identification of 12-oxo-lithocholic acid (BAA485), a potential microbiome-derived bile acid metabolite. We demonstrate that the more potent analogue 11-oxo-12S-hydroxylithocholic acid methyl ester (BAA473) can induce secretion of interleukin-18 (IL-18) through activation of the inflammasome in both myeloid and intestinal epithelial cells. Using a genome-wide CRISPR screen with compound induced pyroptosis in THP-1 cells, we identified that inflammasome activation by BAA473 is pyrin-dependent (MEFV). To our knowledge, the bile acid analogues BAA485 and BAA473 are the first small molecule activators of the pyrin inflammasome. We surmise that pyrin inflammasome activation through microbiota-modified bile acid metabolites such as BAA473 and BAA485 plays a role in gut microbiota regulated intestinal immune response. The discovery of these two bioactive compounds may help to further unveil the importance of pyrin in gut homeostasis and autoimmune diseases.


Subject(s)
Bile Acids and Salts/immunology , Epithelial Cells/immunology , Gastrointestinal Microbiome/immunology , Immunity, Mucosal , Inflammasomes/immunology , Intestinal Mucosa/immunology , Pyrin/immunology , Bile Acids and Salts/chemistry , Humans , Myeloid Cells/immunology , THP-1 Cells
5.
Cell Rep ; 19(3): 451-460, 2017 04 18.
Article in English | MEDLINE | ID: mdl-28423309

ABSTRACT

Flavivirus infections by Zika and dengue virus impose a significant global healthcare threat with no US Food and Drug Administration (FDA)-approved vaccination or specific antiviral treatment available. Here, we present the discovery of an anti-flaviviral natural product named cavinafungin. Cavinafungin is a potent and selectively active compound against Zika and all four dengue virus serotypes. Unbiased, genome-wide genomic profiling in human cells using a novel CRISPR/Cas9 protocol identified the endoplasmic-reticulum-localized signal peptidase as the efficacy target of cavinafungin. Orthogonal profiling in S. cerevisiae followed by the selection of resistant mutants pinpointed the catalytic subunit of the signal peptidase SEC11 as the evolutionary conserved target. Biochemical analysis confirmed a rapid block of signal sequence cleavage of both host and viral proteins by cavinafungin. This study provides an effective compound against the eukaryotic signal peptidase and independent confirmation of the recently identified critical role of the signal peptidase in the replicative cycle of flaviviruses.


Subject(s)
Biological Products/pharmacology , Dengue Virus/physiology , Lipopeptides/pharmacology , Virus Replication/drug effects , Zika Virus/physiology , Biological Products/chemistry , CRISPR-Cas Systems/genetics , Dengue Virus/drug effects , Gene Knockdown Techniques , Genome, Human , Genomics , HCT116 Cells , Humans , Lipopeptides/chemistry , Membrane Proteins , Protein Subunits/metabolism , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Serine Endopeptidases , Viral Proteins/metabolism , Zika Virus/drug effects
6.
Bioorg Med Chem ; 25(3): 921-925, 2017 02 01.
Article in English | MEDLINE | ID: mdl-28011199

ABSTRACT

A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering a novel, unexplored and underrepresented chemical space in fragment based drug discovery (FBDD).


Subject(s)
Biological Products/chemistry , Cytochalasins/chemistry , Lactones/chemistry , Small Molecule Libraries/chemistry , Spiro Compounds/chemistry , Biological Products/chemical synthesis , Crystallography, X-Ray , Cytochalasins/chemical synthesis , Drug Discovery , Lactones/chemical synthesis , Models, Molecular , Molecular Structure , Small Molecule Libraries/chemical synthesis , Spiro Compounds/chemical synthesis
7.
Chem Biol ; 22(1): 87-97, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25544045

ABSTRACT

The highly conserved 70 kDa heat shock proteins (Hsp70) play an integral role in proteostasis such that dysregulation has been implicated in numerous diseases. Elucidating the precise role of Hsp70 family members in the cellular context, however, has been hampered by the redundancy and intricate regulation of the chaperone network, and relatively few selective and potent tools. We have characterized a natural product, novolactone, that targets cytosolic and ER-localized isoforms of Hsp70 through a highly conserved covalent interaction at the interface between the substrate-binding and ATPase domains. Biochemical and structural analyses indicate that novolactone disrupts interdomain communication by allosterically inducing a conformational change in the Hsp70 protein to block ATP-induced substrate release and inhibit refolding activities. Thus, novolactone is a valuable tool for exploring the requirements of Hsp70 chaperones in diverse cellular contexts.


Subject(s)
Abietanes/metabolism , Biological Products/metabolism , HSP70 Heat-Shock Proteins/metabolism , Abietanes/chemistry , Adenosine Triphosphatases/metabolism , Allosteric Regulation , Binding Sites , Biological Products/chemistry , Cell Line , Crystallography, X-Ray , Endoplasmic Reticulum/metabolism , Genome, Fungal , HSP40 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/chemistry , Humans , Molecular Dynamics Simulation , Protein Binding , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Protein Structure, Tertiary , Saccharomyces cerevisiae/genetics , Substrate Specificity
8.
J Antibiot (Tokyo) ; 60(1): 52-60, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17390589

ABSTRACT

The microbial macrolides bafilomycin A1, B, and concanamycin A from Streptomyces spp. are potent and specific inhibitors of V-ATPases. The question of the biosynthetic origin of the two uncommon "glycolate units" of each of the macrolide structures was addressed by feeding experiments with stereospecifically 13C-labeled precursors. Our studies clearly indicate that glycerol is a source for the methoxylated C2-units and determines the orientation of the incorporation. Products from the carboxylic acid pool or TCA cycle are ruled out as key precursors. The data suggest the action of a glycerol kinase and point to phosphoglycerate as an intermediate in their biosynthesis. However, glycerate itself is not accepted as a precursor. We present the likely biosynthetic pathway and show the value of stereospecifically labeled presursors as an important tool for biosynthetic investigations.


Subject(s)
Glycolates/metabolism , Macrolides/metabolism , Streptomyces/metabolism , Carbon Isotopes/metabolism , Carboxylic Acids , Citric Acid Cycle , Glycerol/metabolism , Glycerol Kinase/metabolism , Metabolic Networks and Pathways , Molecular Structure
9.
J Org Chem ; 71(19): 7125-32, 2006 Sep 15.
Article in English | MEDLINE | ID: mdl-16958505

ABSTRACT

The new spiro[4.5]acetal okaspirodiol (4) was isolated from Streptomyces sp. Gö TS 19 as a secondary metabolite in yields up to 380 mg/L. The structure of this cryptic ketotetrol was elucidated by different methods including X-ray analysis, and its equilibration under mildly acidic conditions furnishing three additional isomers was thoroughly studied. Although metabolite 4 is not the thermodynamically favored isomer, a high-yielding total synthesis was accomplished comprising a stereoselective spiroacetalization under equilibrium conditions. This approach benefits from the important influence of an intramolecular hydrogen bond on the stabilization of the spiro[4.5]acetal moiety. The biosynthesis of 4 was investigated by feeding experiments with 13C-labeled precursors proving its origin from a new type of the rare mixed acetate-glycerol biosynthetic pathway. All results are discussed on the basis of the structural diversity of spiroacetals in nature and their chemical properties.


Subject(s)
Spiro Compounds , Streptomyces/metabolism , Acetals/chemical synthesis , Acetals/isolation & purification , Acetals/metabolism , Crystallography, X-Ray , Fermentation , Magnetic Resonance Spectroscopy , Molecular Structure , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/isolation & purification , Spiro Compounds/metabolism , Stereoisomerism
10.
J Antibiot (Tokyo) ; 57(10): 655-61, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15638326

ABSTRACT

The plecomacrolides bafilomycin A1 and B1 (1, 2) and concanamycin A (3), produced by different Streptomyces species, show a unique macrolactone structure with characteristic side chains and exhibit striking biological activities including distinct V-type ATPase inhibition. The biosynthesis of 1 and 2 has been established by feeding experiments with 13C-labelled precursors. Both, bafilomycin (1, 2) and concanamycin (3) feature an "unusual C2 chain extension unit" of as yet unknown origin which was addressed by feeding labelled 2-hydroxy- and 2-methoxymalonyl-derivatives.


Subject(s)
Enzyme Inhibitors/metabolism , Macrolides/metabolism , Streptomyces/metabolism , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors
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