Natural Products as a Foundation for Drug Discovery

Beutler, John A.

doi:10.1002/cpph.67

Cited by 101 publications

(82 citation statements)

References 222 publications

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“…The perception is "the easy compounds have been made, the progress of research is too slow (even in high throughput screening), and the remainder are too difficult." [76] Our laboratory solution is "de novo". From the Latin meaning "of new," it is more directly translated to mean "from the beginning."…”

Section: Discussionmentioning

confidence: 99%

Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from Poecilotheria

Johnson

Rikli

2020

Toxins

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Research in toxinology has created a pharmacological paradox. With an estimated 220,000 venomous animals worldwide, the study of peptidyl toxins provides a vast number of effector molecules. However, due to the complexity of the protein-protein interactions, there are fewer than ten venom-derived molecules on the market. Structural characterization and identification of post-translational modifications are essential to develop biological lead structures into pharmaceuticals. Utilizing advancements in mass spectrometry, we have created a high definition approach that fuses conventional high-resolution MS-MS with ion mobility spectrometry (HDMSE) to elucidate these primary structure characteristics. We investigated venom from ten species of “tiger” spider (Genus: Poecilotheria) and discovered they contain isobaric conformers originating from non-enzymatic Asp isomerization. One conformer pair conserved in five of ten species examined, denominated PcaTX-1a and PcaTX-1b, was found to be a 36-residue peptide with a cysteine knot, an amidated C-terminus, and isoAsp33Asp substitution. Although the isomerization of Asp has been implicated in many pathologies, this is the first characterization of Asp isomerization in a toxin and demonstrates the isomerized product’s diminished physiological effects. This study establishes the value of a HDMSE approach to toxin screening and characterization.

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Section: Discussionmentioning

confidence: 99%

Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from Poecilotheria

Johnson

Rikli

2020

Toxins

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“…In such cases, total organic synthesis can assist. Many synthetic procedures for salvianic acid have been reported including its synthesis from commercially available compounds such as 3,4 dihydroxy benzaldehyde 15,16,19 and its hydrolysis from rosmarinic acid and other natural products with both chemical and enzymatical reactions 17,20,[56][57][58] . Although, these methods suffer from low yields, many reaction steps that diminish the yield and also produce a large amount of waste.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the interaction profile of rosmarinic acid and its bioactive substructures with serum albumin

Papaemmanouil

Chatziathanasiadou

Chatzigiannis

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Rosmarinic acid, a phytochemical compound, bears diverse pharmaceutical profile. It is composed by two building blocks: caffeic acid and a salvianic acid unit. The interaction profile, responsible for the delivery of rosmarinic acid and its two substructure components by serum albumin remains unexplored. To unveil this, we established a novel low-cost and efficient method to produce salvianic acid from the parent compound. To probe the interaction profile of rosmarinic acid and its two substructure constituents with the different serum albumin binding sites we utilised fluorescence spectroscopy and competitive saturation transfer difference NMR experiments. These studies were complemented with transfer NOESY NMR experiments. The thermodynamics of the binding profile of rosmarinic acid and its substructures were addressed using isothermal titration calorimetry. In silico docking studies, driven by the experimental data, have been used to deliver further atomic details on the binding mode of rosmarinic acid and its structural components.

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“…About 35% of these medicines directly or indirectly originated from natural products: animals (~3%), microorganisms (13%), and plants (25%) (Calixto, 2019). A large proportion (7/26) of the antibacterial medicines approved from 2008 to 2018 is derived from natural products (Beutler, 2019). In synthetic drugs, there are also a considerable number of natural products borrowed from the skeleton structure or pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Transcriptome Profiling in Drug and Biomarker Discovery

et al. 2020

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The development of new drugs is multidisciplinary and systematic work. High-throughput techniques based on "-omics" have driven the discovery of biomarkers in diseases and therapeutic targets of drugs. A transcriptome is the complete set of all RNAs transcribed by certain tissues or cells at a specific stage of development or physiological condition. Transcriptome research can demonstrate gene functions and structures from the whole level and reveal the molecular mechanism of specific biological processes in diseases. Currently, gene expression microarray and high-throughput RNA-sequencing have been widely used in biological, medical, clinical, and drug research. The former has been applied in drug screening and biomarker detection of drugs due to its high throughput, fast detection speed, simple analysis, and relatively low price. With the further development of detection technology and the improvement of analytical methods, the detection flux of RNAseq is much higher but the price is lower, hence it has powerful advantages in detecting biomarkers and drug discovery. Compared with the traditional RNA-seq, scRNA-seq has higher accuracy and efficiency, especially the single-cell level of gene expression pattern analysis can provide more information for drug and biomarker discovery. Therefore, (sc) RNA-seq has broader application prospects, especially in the field of drug discovery. In this overview, we will review the application of these technologies in drug, especially in natural drug and biomarker discovery and development. Emerging applications of scRNA-seq and the third generation RNA-sequencing tools are also discussed.

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Natural Products as a Foundation for Drug Discovery

Cited by 101 publications

References 222 publications

Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from Poecilotheria

Aspartic Acid Isomerization Characterized by High Definition Mass Spectrometry Significantly Alters the Bioactivity of a Novel Toxin from Poecilotheria

Unveiling the interaction profile of rosmarinic acid and its bioactive substructures with serum albumin

High-Throughput Transcriptome Profiling in Drug and Biomarker Discovery

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