The fungus Monascus is a well-known source of secondary metabolites with interesting pharmaceutical and nutraceutical applications. In particular, Monascus pigments possess a wide range of biological activities (e.g. antimicrobial, antioxidant, anti-inflammatory or antitumoral). To broaden the scope of their possible application, this study focused on testing Monascus pigment extracts as potential photosensitizing agents efficient in antimicrobial photodynamic therapy (aPDT) against bacteria. For this purpose, eight different extracts of secondary metabolites from the liquid- and solid-state fermentation of Monascus purpureus DBM 4360 and Monascus sp. DBM 4361 were tested against Gram-positive and Gram-negative model bacteria, Bacillus subtilis and Escherichia coli and further screened for ESKAPE pathogens, Staphylococcus aureus and Pseudomonas aeruginosa. To the bacterial culture, increasing concentration of extracts was added and it was found that all extracts showed varying antimicrobial activity against Gram-positive bacteria in dark, which was further increased after irradiation. Gram-negative bacteria were tolerant to the extracts' exposure in the dark but sensitivity to almost all extracts that occurred after irradiation. The Monascus sp. DBM 4361 extracts seemed to be the best potential candidate for aPDT against Gram-positive bacteria, being efficient at low doses, i.e. the lowest total concentration of Monascus pigments exhibiting aPDT effect was 3.92 ± 1.36 mg/L for E. coli. Our results indicate that Monascus spp., forming monascuspiloin as the major yellow pigment and not-forming mycotoxin citrinin, is a promising source of antimicrobials and photoantimicrobials.
- MeSH
- antibakteriální látky * farmakologie chemie MeSH
- biologické pigmenty farmakologie MeSH
- biologické přípravky farmakologie chemie MeSH
- fotochemoterapie MeSH
- fotosenzibilizující látky farmakologie chemie MeSH
- grampozitivní bakterie účinky léků účinky záření MeSH
- komplexní směsi farmakologie chemie MeSH
- mikrobiální testy citlivosti * MeSH
- Monascus * chemie metabolismus MeSH
- mycelium * chemie účinky záření účinky léků MeSH
- Publikační typ
- časopisecké články MeSH
Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC50 values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. Reduced antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2); however, a synergistic improvement in antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy.
- MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- biologické přípravky chemická syntéza chemie farmakologie MeSH
- buňky A549 MeSH
- Cercopithecus aethiops MeSH
- COVID-19 metabolismus MeSH
- farmakoterapie COVID-19 MeSH
- inhibitory cysteinových proteinas chemická syntéza chemie farmakologie MeSH
- kathepsin L antagonisté a inhibitory metabolismus MeSH
- kationické antimikrobiální peptidy chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární konformace MeSH
- proteomika MeSH
- SARS-CoV-2 účinky léků MeSH
- Vero buňky MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Microbial biofilm is a major source of problems and microbial contamination across the industrial production, for example in pharmacy, agriculture orfood industry, but also in healthcare. One of the possible solutions to this problem is the inhibition of its formation or eradication of the already formed biofilm. There are many ways to achieve this goal. This review article focuses on the use of chemical disinfectants, antibiotics or biologically active natural substances.
This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.
- MeSH
- antiinfekční látky chemická syntéza chemie farmakologie MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- biologické přípravky chemie farmakologie MeSH
- cholestanoly chemie MeSH
- cholestany chemie MeSH
- inhibitory angiogeneze chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- spermin analogy a deriváty chemie MeSH
- steroidy chemická syntéza chemie farmakologie MeSH
- triterpeny chemická syntéza chemie farmakologie MeSH
- vodní organismy chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action.
- MeSH
- antibakteriální látky * chemie farmakologie MeSH
- antiflogistika * chemie farmakologie MeSH
- antioxidancia * chemie farmakologie MeSH
- antitumorózní látky * chemie farmakologie MeSH
- biologické přípravky * chemie farmakologie MeSH
- buněčné linie MeSH
- chalkonoidy * chemie farmakologie MeSH
- lidé MeSH
- objevování léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Covering: up to the end of 2020. The machine learning field can be defined as the study and application of algorithms that perform classification and prediction tasks through pattern recognition instead of explicitly defined rules. Among other areas, machine learning has excelled in natural language processing. As such methods have excelled at understanding written languages (e.g. English), they are also being applied to biological problems to better understand the "genomic language". In this review we focus on recent advances in applying machine learning to natural products and genomics, and how those advances are improving our understanding of natural product biology, chemistry, and drug discovery. We discuss machine learning applications in genome mining (identifying biosynthetic signatures in genomic data), predictions of what structures will be created from those genomic signatures, and the types of activity we might expect from those molecules. We further explore the application of these approaches to data derived from complex microbiomes, with a focus on the human microbiome. We also review challenges in leveraging machine learning approaches in the field, and how the availability of other "omics" data layers provides value. Finally, we provide insights into the challenges associated with interpreting machine learning models and the underlying biology and promises of applying machine learning to natural product drug discovery. We believe that the application of machine learning methods to natural product research is poised to accelerate the identification of new molecular entities that may be used to treat a variety of disease indications.
- MeSH
- biologické přípravky * chemie farmakologie MeSH
- biosyntetické dráhy genetika MeSH
- genomika * MeSH
- lidé MeSH
- mikrobiota MeSH
- objevování léků MeSH
- strojové učení * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Ecdysteroids (ECs) are steroid hormones originally found in the animal kingdom where they function as insect molting hormones. Interestingly, a relatively high number of these substances can also be formed in plant cells. Moreover, ECs have certain regulatory effects on plant physiology, but their role in plants still requires further study. One of the main aims of the present study was to verify a hypothesis that fenarimol, an inhibitor of the biosynthesis of ECs in the animal kingdom, also affects the content of endogenous ECs in plants using winter wheat Triticum aestivum L. as a model plant. The levels of endogenous ECs in winter wheat, including the estimation of their changes during a course of different temperature treatments, have been determined using a sensitive analytical method based on UHPLC-MS/MS. Under our experimental conditions, four substances of EC character were detected in the tissue of interest in amounts ranging from less than 1 to over 200 pg·g-1 FW: 20-hydroxyecdysone, polypodine B, turkesterone, and isovitexirone. Among them, turkesterone was observed to be the most abundant EC and accumulated mainly in the crowns and leaves of wheat. Importantly, the level of ECs was observed to be dependent on the age of the plants, as well as on growth conditions (especially temperature). Fenarimol, an inhibitor of a cytochrome P450 monooxygenase, was shown to significantly decrease the level of naturally occurring ECs in experimental plants, which may indicate its potential use in studies related to the biosynthesis and physiological function of these substances in plants.
- MeSH
- biologické přípravky chemie metabolismus MeSH
- chromatografie kapalinová metody MeSH
- ekdysteroidy biosyntéza chemie MeSH
- fungicidy průmyslové farmakologie MeSH
- listy rostlin účinky léků metabolismus MeSH
- molekulární struktura MeSH
- pšenice růst a vývoj metabolismus MeSH
- pyrimidiny farmakologie MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- teplota MeSH
- Publikační typ
- časopisecké články MeSH
Calanolides are tetracyclic 4-substituted dipyranocoumarins. Calanolide A, isolated from the leaves and twigs of Calophyllum lanigerum var. austrocoriaceum (Whitmore) P. F. Stevens, is the first member of this group of compounds with anti-HIV-1 activity mediated by reverse transcriptase inhibition. Calanolides are classified pharmacologically as non-nucleoside reverse transcriptase inhibitors (NNRTI). There are at least 15 naturally occurring calanolides distributed mainly within the genus Calophyllum, but some of them are also present in the genus Clausena. Besides significant anti-HIV properties, which have been exploited towards potential development of new NNRTIs for anti-HIV therapy, calanolides have also been found to possess anticancer, antimicrobial and antiparasitic potential. This review article provides a comprehensive update on all aspects of naturally occurring calanolides, including their chemistry, natural occurrence, biosynthesis, pharmacological and toxicological aspects including mechanism of action and structure activity relationships, pharmacokinetics, therapeutic potentials and available patents.
- MeSH
- biologické přípravky chemie metabolismus farmakologie terapeutické užití MeSH
- lidé MeSH
- pyranokumariny chemie metabolismus farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls-hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.
- MeSH
- Bacteria chemie MeSH
- biologické přípravky chemie MeSH
- indoly chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární mimikry MeSH
- objevování léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Matrix-Liposomes (MLs) are a very promising solid oral drug delivery system; however, data on their interaction with biological membranes are not available. Here, we describe the quality of MLs manufactured by dual centrifugation. MLs were prepared with a Z-average range of 139 to 160 nm and a PDI of 0.18 to 0.25. To investigate the effect of MLs on intestinal tissue (with and without mucolytic treatment), we then established an ex vivo rat intestine model. The integrity of the epithelial membranes of rat intestine was not affected by the incubation with MLs without or with pre-mucolytic treatment. Tissue samples were also analysed for changes in P-glycoprotein (P-gp) expression and function. The net secretion of the P-gp substrate Rh123 across the rat duodenum was increased in the presence of MLs. To summarize, MLs do not affect intestinal epithelial integrity, although they impact Rh123 secretion. In future, these novel MLs have to be further evaluated for proficient intestinal drug delivery.
- MeSH
- biologické přípravky chemie MeSH
- biologický transport fyziologie MeSH
- duodenum metabolismus MeSH
- intestinální absorpce fyziologie MeSH
- krysa rodu rattus MeSH
- liposomy chemie MeSH
- P-glykoprotein metabolismus MeSH
- střevní sliznice metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
