Birgit Waltenberger

Discovery and resupply of pharmacologically active plant-derived natural products: A review.

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.

Graphical abstract

Pharmacophore Modeling and Virtual Screening for Novel Acidic Inhibitors of Microsomal Prostaglandin E2 Synthase-1 (mPGES-1)

Microsomal prostaglandin E2 synthase-1 (mPGES-1) catalyzes prostaglandin E2 formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC50 values between 0.4 and 7.9 μM, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC50 values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGES-1 are presented that may possess anti-inflammatory properties based on the interference with eicosanoid biosynthesis.

Natural Products to Counteract the Epidemic of Cardiovascular and Metabolic Disorders

Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an “opening” of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease.

Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo.

The transcription factor NF‐κB orchestrates many pro‐inflammatory signals and its inhibition is considered a promising strategy to combat inflammation. Here we report the characterization of the natural product plumericin as a highly potent inhibitor of the NF‐κB pathway with a novel chemical scaffold, which was isolated via a bioactivity‐guided approach, from extracts of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation‐related disorders.

Discovery of depsides and depsidones from lichen as potent inhibitors of microsomal prostaglandin E2 synthase-1 using pharmacophore models.

Nature in silico: Virtual screening using validated pharmacophore models identified lichen depsides and depsidones as potential inhibitors of mPGES-1, an emerging target for NSAIDs. Evaluation of the virtual hits in a cell-free assay revealed physodic acid and perlatolic acid as potent inhibitors of mPGES-1 (IC(50) = 0.4 and 0.43 μM, respectively), indicating that these natural products have potential as novel anti-inflammatory agents.

Predicting Cyclooxygenase Inhibition by Three-Dimensional Pharmacophoric Profiling. Part I: Model Generation, Validation and Applicability in Ethnopharmacology.

3D pharmacophore modeling has evolved as an established and state‐of‐the‐art method for performing in‐silico predictions of biological activity. Using one single model is limited to single binding modes, while the combination of several models bears a broader application scope. We demonstrate the generation of a complete and predictive 3D model set for cyclooxygenase 1 and 2 inhibitors, along with a selection and validation protocol optimized for parallel virtual screening. This model set was applied to explain the cyclooxygenase activity of an ethnopharmacologically known mixture of natural products, the Thai traditional medicine “Prasaplai”. Results show that rationalizing natural product activity by modern in‐silico approaches is promising and can be tremendously useful in the identification of the mechanisms of action for known biological effects of complex herbal remedies.

Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn’s disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.

Plumericin inhibits proliferation of vascular smooth muscle cells by blocking STAT3 signaling via S-glutathionylation

The etiology of atherosclerosis and restenosis involves aberrant inflammation and proliferation, rendering compounds with both anti-inflammatory and anti-mitogenic properties as promising candidates for combatting vascular diseases. A recent study identified the iridoid plumericin as a new scaffold inhibitor of the pro-inflammatory NF-κB pathway in endothelial cells. We here examined the impact of plumericin on the proliferation of primary vascular smooth muscle cells (VSMC). Plumericin inhibited serum-stimulated proliferation of rat VSMC. It arrested VSMC in the G1/G0-phase of the cell cycle accompanied by abrogated cyclin D1 expression and hindered Ser 807/811-phosphorylation of retinoblastoma protein. Transient depletion of glutathione by the electrophilic plumericin led to S-glutathionylation as well as hampered Tyr705-phosphorylation and activation of the transcription factor signal transducer and activator of transcription 3 (Stat3). Exogenous addition of glutathione markedly prevented this inhibitory effect of plumericin on Stat3. It also overcame downregulation of cyclin D1 expression and the reduction of biomass increase upon serum exposure. This study revealed an anti-proliferative property of plumericin towards VSMC which depends on plumericin’s thiol reactivity and S-glutathionylation of Stat3. Hence, plumericin, by targeting at least two culprits of vascular dysfunction –inflammation and smooth muscle cell proliferation -might become a promising electrophilic lead compound for vascular disease therapy.

Discovery of Potent Soluble Epoxide Hydrolase (sEH) Inhibitors by Pharmacophore-Based Virtual Screening.

There is an increasing interest in the development of soluble epoxide hydrolase (sEH) inhibitors, which block the degradation of endogenous anti-inflammatory epoxyeicosatrienoic acids. Within this study, a set of pharmacophore models for sEH inhibitors was developed. The Specs database was virtually screened and a cell-free sEH activity assay was used for the biological investigation of virtual hits. In total, out of 48 tested compounds, 19 were sEH inhibitors with IC50 < 10 μM, representing a prospective true positive hit rate of 40%. Six of these compounds displayed IC50 values in the low nanomolar range. The most potent compound 21, a urea derivative, inhibited sEH with an IC50 = 4.2 nM. The applied approach also enabled the identification of diverse chemical scaffolds, e.g. the pyrimidinone derivative 29 (IC50 = 277 nM). The generated pharmacophore model set therefore represents a valuable tool for the selection of compounds for biological testing.