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Sinomenine is the main component of the vine Sinomenium acutum . It was first isolated in the early 1920s and has since attracted special interest as a potential anti-rheumatoid arthritis (RA) agent, owing to its successful application in traditional Chinese medicine for the treatment of neuralgia and rheumatoid diseases. In the past few decades, significant advances have broadened our understanding of the molecular mechanisms through which sinomenine treats RA, as well as the structural modifications necessary for improved pharmacological activity. In this review, we summarize up-to-date reports on the pharmacological properties of sinomenine in RA treatment, document their underlying mechanisms, and provide an overview of promising sinomenine derivatives as potential RA drug therapies.

The composition of serum is extremely complex, which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis. Recently, nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum. Here, we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona (PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis. We identified 1,070 proteins with a median coefficient of variation of 12.56% using PC-based proteomic analysis, which was twice the number of proteins identified by direct digestion. There were also more biological processes enriched with these proteins. We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis (CIA) rat model treated with methotrexate (MTX). The bioinformatic results indicated that 485 differentially expressed proteins (DEPs) were found in CIA rats, of which 323 DEPs recovered to near normal levels after treatment with MTX. This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies, but also provide more pharmacodynamic biomarkers for disease prediction, diagnosis, and treatment., Competing Interests: The authors declare that there are no conflicts of interest., (© 2022 The Authors.)

Artemisinins are a family of sesquiterpene lactones originally derived from the sweet wormwood (Artemisia annua). Beyond their well-characterized role as frontline antimalarial drugs, artemisinins have also received increased attention for other potential pharmaceutical effects, which include antiviral, antiparsitic, antifungal, anti-inflammatory, and anticancer activities. With concerted efforts in further preclinical and clinical studies, artemisinin-based drugs have the potential to be viable treatments for a great variety of human diseases. Here, we provide a comprehensive update on recent reports of pharmacological actions and applications of artemisinins outside of their better-known antimalarial role and highlight their potential therapeutic viability for various diseases., (© 2021 Wiley Periodicals LLC.)

Fragment screening is a powerful drug discovery approach particularly useful for enzymes difficult to inhibit selectively, such as the thiol/selenol-dependent thioredoxin reductases (TrxRs), which are essential and druggable in several infectious diseases. Several known inhibitors are reactive electrophiles targeting the selenocysteine-containing C-terminus and thus often suffering from off-target reactivity in vivo . The lack of structural information on the interaction modalities of the C-terminus-targeting inhibitors, due to the high mobility of this domain and the lack of alternative druggable sites, prevents the development of selective inhibitors for TrxRs. In this work, fragments selected from actives identified in a large screen carried out against Thioredoxin Glutathione Reductase from Schistosoma mansoni (SmTGR) were probed by X-ray crystallography. SmTGR is one of the most promising drug targets for schistosomiasis, a devastating, neglected disease. Utilizing a multicrystal method to analyze electron density maps, structural analysis, and functional studies, three binding sites were characterized in SmTGR: two sites are close to or partially superposable with the NADPH binding site, while the third one is found between two symmetry related SmTGR subunits of the crystal lattice. Surprisingly, one compound bound to this latter site stabilizes, through allosteric effects mediated by the so-called guiding bar residues, the crucial redox active C-terminus of SmTGR, making it finally visible at high resolution. These results further promote fragments as small molecule probes for investigating functional aspects of the target protein, exemplified by the allosteric effect on the C-terminus, and providing fundamental chemical information exploitable in drug discovery.

Schistosomiasis is a widespread human parasitic disease currently affecting over 200 million people. Chemotherapy for schistosomiasis relies exclusively on praziquantel. Although significant advances have been made in recent years to reduce the incidence and intensity of schistosome infections, these gains will be at risk should drug-resistant parasites evolve. Thioredoxin glutathione reductase (TGR) is a selenoprotein of the parasite essential for the survival of schistosomes in the mammalian host. Several high-throughput screening campaigns have identified inhibitors of Schistosoma mansoni TGR. Follow up analyses of select active compounds form the basis of the present study. We identified eight compounds effective against ex vivo worms. Compounds 1 - 5 are active against all major species and development stages. The ability of these compounds to target immature worms is especially critical because praziquantel is poorly active against this stage. Compounds 1 - 5 , 7 , and 8 displayed schistosomicidal activity even after only 1 h incubation with the worms. Compounds 1 - 4 meet or exceed standards set by the World Health Organization for leads for schistosomiasis therapy activity. The mechanism of TGR inhibition was studied further with wild-type and mutant TGR proteins. Compounds 4 - 6 were found to induce an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in TGR, leading to the production of superoxide and hydrogen peroxide. Collectively, this effort has identified several active compound series that may serve as the basis for the development of new schistosomicidal compounds.

Selective suicide inhibitors represent a seductively attractive approach for inactivation of therapeutically relevant enzymes since they are generally devoid of off-target toxicity in vivo. While most suicide inhibitors are converted to reactive species at enzyme active sites, theoretically bioactivation can also occur in ectopic (secondary) sites that have no known function. Here, we report an example of such an "ectopic suicide inhibition", an unprecedented bioactivation mechanism of a suicide inhibitor carried out by a non-catalytic site of thioredoxin glutathione reductase (TGR). TGR is a promising drug target to treat schistosomiasis, a devastating human parasitic disease. Utilizing hits selected from a high throughput screening campaign, time-resolved X-ray crystallography, molecular dynamics, mass spectrometry, molecular modeling, protein mutagenesis and functional studies, we find that 2-naphtholmethylamino derivatives bound to this novel ectopic site of Schistosoma mansoni (Sm)TGR are transformed to covalent modifiers and react with its mobile selenocysteine-containing C-terminal arm. In particular, one 2-naphtholmethylamino compound is able to specifically induce the pro-oxidant activity in the inhibited enzyme. Since some 2-naphtholmethylamino analogues show worm killing activity and the ectopic site is not conserved in human orthologues, a general approach to development of novel and selective anti-parasitic therapeutics against schistosoma is proposed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off-target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectively inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms, the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases.

By disruption of LaeB, a global regulator recently characterized in Aspergillus nidulans, eight cryptic compounds in the mutant were identified, including seven polyketides and one NRPS-like product. Among the isolates, two phthalides and two dibenzo[1,4]dioxins are new compounds, revealing that the genetic manipulation of the global regulator represents a promising approach for the discovery of novel natural products in fungi.

Aurovertins are the structurally diverse polyketides that distribute widely in different fungal species. They feature a 2,6-dioxabicyclo[3.2.1]-octane ring in structure and exhibit the potential antitumor activity against breast cancer as F1-ATPase β subunit inhibitor. In this study, we constructed the biosynthetic pathway of aurovertin in an Aspergillus nidulans host and obtained seven aurovertin-type compounds. Surprisingly, three new aurovertin geometric isomers were characterized. By introducing an inducible promoter xylP(p) in the pathway gene acyltransferase aurG, we can control the product ratios among different aurovertin compounds by adding glucose and/or inducer xylose. The yields of aurovertins could be increased up to about 20 times by adding a constitutive promoter gpdA(p) to transcription factor AurF, which indicates AurF's positive role in the biosynthesis of aurovertin. Taken together, our results provided not only an efficient way to generate bioactive fungal natural products but also realized the rational controlling their yields with designed promoters.

By deleting the COP9 signalosome subunit PfcsnE from Pestalotiopsis fici, seven compounds that were newly produced by the mutant could be characterized, including five new structures, pestaloficins A-E (1 and 3-6). Pestaloficin A (1) represents a new type of dimeric cyclohexanone derivative linked through an unprecedented pentacyclic spiral ring.