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ApoA-I Nanoparticles as Curcumin Carriers for Cerebral Endothelial Cells: Improved Cytoprotective Effects against Methylglyoxal
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In Vivo Imaging of Rat Vascularity with FDG-Labeled Erythrocytes
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Association between Proton Pump Inhibitor Use and Parkinson’s Disease in a Korean Population
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Pharmaceutically Active Microbial AhR Agonists as Innovative Biodrugs in Inflammation
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COVID-19 and Seasonal Influenza Vaccination: Cross-Protection, Co-Administration, Combination Vaccines, and Hesitancy
Journal Description
Pharmaceuticals
Pharmaceuticals
is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is partners of Pharmaceuticals and their members receive a discount on the article processing charge.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and many other databases.
- Journal Rank: JCR - Q1 (Pharmacology & Pharmacy) / CiteScore - Q2 (Pharmaceutical Science)
- Rapid Publication: manuscripts are peer-reviewed and a first decision provided to authors approximately 14.7 days after submission; acceptance to publication is undertaken in 2.9 days (median values for papers published in this journal in the second half of 2021).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Testimonials: See what our authors say about Pharmaceuticals
- International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
- Companion journals for Pharmaceuticals include: Pharmacoepidemiology and Psychoactives.
Impact Factor:
5.863 (2020)
;
5-Year Impact Factor:
5.85 (2020)
Latest Articles
A Combination of Pharmacophore-Based Virtual Screening, Structure-Based Lead Optimization, and DFT Study for the Identification of S. epidermidis TcaR Inhibitors
Pharmaceuticals 2022, 15(5), 635; https://doi.org/10.3390/ph15050635 - 21 May 2022
Abstract
The transcriptional regulator (TcaR) enzyme plays an important role in biofilm formation. Prevention of TcaR-DNA complex formation leads to inhibit the biofilm formation is likely to reveal therapeutic ways for the treatment of bacterial infections. To identify the novel ligands for TcaR and
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The transcriptional regulator (TcaR) enzyme plays an important role in biofilm formation. Prevention of TcaR-DNA complex formation leads to inhibit the biofilm formation is likely to reveal therapeutic ways for the treatment of bacterial infections. To identify the novel ligands for TcaR and to provide a new idea for drug design, two efficient drug design methods, such as pharmacophore modeling and structure-based drug design, were used for virtual screening of database and lead optimization, respectively. Gemifloxacin (FDA-approved drug) was considered to generate the pharmacophore model for virtual screening of the ZINC database, and five hits, namely ZINC77906236, ZINC09550296, ZINC77906466, ZINC09751390, and ZINC01269201, were identified as novel inhibitors of TcaR with better binding energies. Using structure-based drug design, a set of 7a–7p inhibitors of S. epidermidis were considered, and Mol34 was identified with good binding energy and high fitness score with improved pharmacological properties. The active site residues ARG110, ASN20, HIS42, ASN45, ALA38, VAL63, VAL68, ALA24, VAL43, ILE57, and ARG71 are playing a promising role in inhibition process. In addition, we performed DFT simulations of final hits to understand the electronic properties and their significant role in driving the inhibitor to adopt apposite bioactive conformations in the active site. Conclusively, the newly identified and designed hits from both the methods are promising inhibitors of TcaR, which can hinder biofilm formation.
Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)
Open AccessSystematic Review
Safety of Short-Term Treatments with Oral Chloroquine and Hydroxychloroquine in Patients with and without COVID-19: A Systematic Review
by
, , , , , , , and
Pharmaceuticals 2022, 15(5), 634; https://doi.org/10.3390/ph15050634 - 21 May 2022
Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other
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Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other drugs. Following the PRISMA and SWiM recommendations, a search was conducted using four health databases for all relevant English-, Chinese-, and Spanish-language studies from inception through 30 July 2021. Patients treated for any condition and with any comparator were included. The outcomes of interest were early drug adverse effects and their frequency. A total of 254 articles met the inclusion criteria, including case and case-control reports as well as cross-sectional, cohort, and randomised studies. The results were summarised either qualitatively in table or narrative form or, when possible (99 studies), quantitatively in terms of adverse event frequencies. Quality evaluation was conducted using the CARE, STROBE, and JADAD tools. This systematic review showed that safety depended on drug indication. In COVID-19 patients, cardiac adverse effects, such as corrected QT interval prolongation, were relatively frequent (0–27.3% and up to 33% if combined with azithromycin), though the risk of torsade de pointes was low. Compared to non-COVID-19 patients, COVID-19 patients experienced a higher frequency of cardiac adverse effects regardless of the regimen used. Dermatological adverse effects affected 0–10% of patients with autoimmune diseases and COVID-19. A broad spectrum of neuropsychiatric adverse effects affected patients treated with CQ for malaria with variable frequencies and some cases were reported in COVID-19 patients. Gastrointestinal adverse effects occurred regardless of drug indication affecting 0–50% of patients. In conclusion, CQ and HCQ are two safe drugs widely used in the treatment of malaria and autoimmune diseases. However, recent findings on their cardiac and neuropsychiatric adverse effects should be considered if these drugs were to be proposed as antivirals again.
Full article
(This article belongs to the Section Pharmacology)
Open AccessArticle
Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
by
, , , and
Pharmaceuticals 2022, 15(5), 633; https://doi.org/10.3390/ph15050633 - 21 May 2022
Abstract
Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the
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Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the downregulation of c-Met by artonin F, a flavonoid isolated from Artocarpus gomezianus. Artonin F was found to be dominantly toxic to lung cancer cells by mediating apoptosis. With regard to its mechanism of action, artonin F downregulated c-Met expression, consequently suppressed the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling, increased Bax expression, decreased Bcl-2 expression, and activated caspase-3. The depletion of c-Met was mediated by ubiquitin-proteasomal degradation following co-treatment with artonin F, with the proteasome inhibitor MG132 reversing its c-Met-targeting effect. The immunoprecipitation analysis revealed that artonin F significantly promoted the formation of the c-Met–ubiquitin complex. Given that ubiquitin-specific protease 8 (USP8) prevents c-Met degradation by deubiquitination, we performed a preliminary in silico molecular docking and observed that artonin F blocked the catalytic site of USP8. In addition, artonin F interacted with the catalytic residues of palmitoylating enzymes. By acting as a competitive inhibitor, artonin F could reduce the degree of palmitoylation of c-Met, which affected its stability and activity. In conclusion, c-Met is critical for cancer cell survival and the failure of chemotherapeutic regimens. This novel information on the c-Met downregulating effect of artonin F will be beneficial for the development of efficient anticancer strategies or targeted therapies.
Full article
(This article belongs to the Special Issue Protein Kinases and Cancer)
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Open AccessArticle
Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors
by
, , , , , , , , and
Pharmaceuticals 2022, 15(5), 632; https://doi.org/10.3390/ph15050632 - 20 May 2022
Abstract
In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common
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In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)-approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-meta-positioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t½ > 120 min) makes it a potential preclinical candidate.
Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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Open AccessCommunication
Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade
by
, , , , , , and
Pharmaceuticals 2022, 15(5), 631; https://doi.org/10.3390/ph15050631 - 20 May 2022
Abstract
Background: Neuropeptide S (NPS) is a multifunctional regulatory factor that exhibits a potent anxiolytic activity in animal models. However, there are no reports dealing with the potential molecular interactions between the activity of selective serotonin reuptake inhibitors (SSRIs) and NPS signaling, especially in
[...] Read more.
Background: Neuropeptide S (NPS) is a multifunctional regulatory factor that exhibits a potent anxiolytic activity in animal models. However, there are no reports dealing with the potential molecular interactions between the activity of selective serotonin reuptake inhibitors (SSRIs) and NPS signaling, especially in the context of adult neurogenesis and the expression of noncanonical stress-related neuropeptides such as neuromedin U (NMU). The present work therefore focused on immunoexpression of neuromedin U receptor 2 (NMUR2) and doublecortin (DCX) in the rat hippocampus after acute treatment with escitalopram and in combination with selective neuropeptide S receptor (NPSR) blockade. Methods: Studies were carried out on adult, male Sprague-Dawley rats that were divided into five groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 10 mg/kg daily), escitalopram + SHA-68, a selective NPSR antagonist (at single dose 40 mg/kg), SHA-68 alone, and corresponding vehicle control. All animals were sacrificed under halothane anaesthesia. The whole hippocampi were quickly excised, fixed, and finally sliced for general qualitative immunohistochemical assessment of the NPSR and NMUR2 expression. The number of immature neurons was enumerated using immunofluorescent detection of doublecortin (DCX) expression within the subgranular zone (SGZ). Results: Acute escitalopram administration affects the number of DCX and NMUR2-expressing cells in the adult rat hippocampus. A decreased number of DCX-expressing neuroblasts after treatment with escitalopram was augmented by SHA-68 coadministration. Conclusions: Early pharmacological effects of escitalopram may be at least partly connected with local NPSR-related alterations of neuroblast maturation in the rat hippocampus. Escitalopram may affect neuropeptide and DCX-expression starting even from the first dose. Adult neurogenesis may be regulated via paracrine neuropeptide S and NMU-related signaling.
Full article
(This article belongs to the Section Pharmacology)
Open AccessArticle
Antifungal Drug Plasma Exposures: A Possible Contribution of Vitamin D-Related Gene Variants
by
, , , , , , , , , , , and
Pharmaceuticals 2022, 15(5), 630; https://doi.org/10.3390/ph15050630 - 20 May 2022
Abstract
Vitamin D (VD) seems to influence drug clearance and outcome. Antifungal drugs (AFU) are the most used azoles in clinical practice. In the literature, no data are available concerning VD’s impact on AFU therapy. The aim of this study was to analyze if
[...] Read more.
Vitamin D (VD) seems to influence drug clearance and outcome. Antifungal drugs (AFU) are the most used azoles in clinical practice. In the literature, no data are available concerning VD’s impact on AFU therapy. The aim of this study was to analyze if VD pathway-related polymorphisms may influence voriconazole (VRC), itraconazole (ITC), and posaconazole (PSC) drug concentrations in order to identify patients with the highest probability of response and toxicity. Allelic discrimination was performed through real-time PCR, whereas drug concentrations were through liquid chromatography. A total of 636 samples of AFU-treated patients were included in the analysis. Concerning VRC, concentrations higher than the 1000 ng/mL efficacy cut-off value were predicted by Caucasian ethnicity, CYP24A1 3999, and CYP27B1 + 2838 polymorphisms, whereas levels higher than the 5000 ng/mL toxicity value by Caucasian, female sex, e.v. administration, and GC 1296. Considering PSC, concentrations higher than the 700 ng/mL efficacy cut-off value were predicted by VDR Cdx2, CYP27B1 − 1260, and GC 1296. Finally, for ITC, VDR BsmI was the only predictor of drug exposure higher than the 500 ng/mL efficacy cut-off value, whereas female sex, CYP27B1 − 1260, and VDR TaqI remained in the final regression model related to concentrations higher than the 1000 ng/mL toxicity-associated cut-off value. This is the first study reporting the influence of VD pathway-related gene SNPs on AFU exposures, efficacy, and toxicity.
Full article
(This article belongs to the Section Pharmacology)
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Open AccessArticle
Supercritical Fluid Chromatography—Tandem Mass Spectrometry for Rapid Quantification of Pentacyclic Triterpenoids in Plant Extracts
by
, , , , and
Pharmaceuticals 2022, 15(5), 629; https://doi.org/10.3390/ph15050629 - 20 May 2022
Abstract
Pentacyclic triterpenoids (PCTs) are a widely distributed class of plant secondary metabolites. These compounds have high bioactive properties, primarily antitumor and antioxidant activity. In this study, a method was developed for the quantitative analysis of pentacyclic triterpenoids in plants using supercritical fluid chromatography–tandem
[...] Read more.
Pentacyclic triterpenoids (PCTs) are a widely distributed class of plant secondary metabolites. These compounds have high bioactive properties, primarily antitumor and antioxidant activity. In this study, a method was developed for the quantitative analysis of pentacyclic triterpenoids in plants using supercritical fluid chromatography–tandem mass spectrometry (SFC-MS/MS). Separation of ten major PCTs (friedelin, lupeol, β-amyrin, α-amyrin, betulin, erythrodiol, uvaol, betulinic, oleanolic and ursolic acids) was studied on six silica-based reversed stationary phases. The best results (7 min analysis time in isocratic elution mode) were achieved on an HSS C18 SB stationary phase using carbon dioxide—isopropanol (8%) mobile phase providing decisive contribution of polar interactions to the retention of analytes. It was shown that the use of atmospheric pressure chemical ionization (APCI) is preferred over atmospheric pressure photoionization (APPI). The combination of SFC with APCI-MS/MS mass spectrometry made it possible to achieve the limits of quantification in plant extracts in the range of 2.3–20 μg·L−1. The developed method was validated and tested in the analyses of birch outer layer (Betula pendula) bark, and licorice (Glycyrrhiza glabra) root, as well as lingonberry (Vaccinium vitis-idaea), cranberry (Vaccinium oxycoccos), apple (Malus domestica “Golden Delicious” and Malus domestica “Red Delicious”) peels.
Full article
(This article belongs to the Special Issue Liquid Chromatography in Analysis of Bioactive Compounds for Pharmaceuticals, Cosmetics, and Functional Food Interest)
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Open AccessArticle
Spray-Drying Encapsulation of the Live Biotherapeutic Candidate Akkermansia muciniphila DSM 22959 to Survive Aerobic Storage
by
, , , , , and
Pharmaceuticals 2022, 15(5), 628; https://doi.org/10.3390/ph15050628 - 20 May 2022
Abstract
Akkermansia muciniphila is regarded as a promising next-generation probiotic or live biotherapeutic candidate. Effective delivery strategies must be developed to ensure high enough viability of the probiotic strain throughout its industrial formulation, distribution chain, shelf-life, and, ultimately, the host’s gastrointestinal tract, where it
[...] Read more.
Akkermansia muciniphila is regarded as a promising next-generation probiotic or live biotherapeutic candidate. Effective delivery strategies must be developed to ensure high enough viability of the probiotic strain throughout its industrial formulation, distribution chain, shelf-life, and, ultimately, the host’s gastrointestinal tract, where it should exert its beneficial effect(s). Among the possible methodologies, spray-drying is considered industrially attractive regarding its costs, efficiency, and scalability, with the due parameter customization. In this study, spray-drying was explored as a one-step process to encapsulate A. muciniphila DSM 22959, testing the drying settings and three different dairy-based matrices. Microcapsule morphology and size was assessed, and viability throughout storage at 4 or 22 °C and simulated gastrointestinal passage was determined. Akkermansia muciniphila microencapsulation by spray-drying, using 10% skim milk and inlet/outlet temperatures of 150/65 °C, is effective in terms of viability stabilization, both during prolonged aerobic storage and exposure to simulated gastrointestinal passage. Akkermansia muciniphila viability was maintained at around 107 CFU/g up to 28 days at 4 °C under aerobic conditions with viability losses inferior to 1 log reduction. This methodology provides the necessary conditions to efficiently deliver the recommended dose of live A. muciniphila in the human gut as a live biotherapeutic product.
Full article
(This article belongs to the Section Pharmaceutical Technology)
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Open AccessArticle
Rhinacanthin-C but Not -D Extracted from Rhinacanthus nasutus (L.) Kurz Offers Neuroprotection via ERK, CHOP, and LC3B Pathways
by
, , , and
Pharmaceuticals 2022, 15(5), 627; https://doi.org/10.3390/ph15050627 - 20 May 2022
Abstract
Neurodegenerative diseases present an increasing problem as the world’s population ages; thus, the discovery of new drugs that prevent diseases such as Alzheimer’s, and Parkinson’s diseases are vital. In this study, Rhinacanthin-C and -D were isolated from Rhinacanthus nasustus, using ethyl acetate,
[...] Read more.
Neurodegenerative diseases present an increasing problem as the world’s population ages; thus, the discovery of new drugs that prevent diseases such as Alzheimer’s, and Parkinson’s diseases are vital. In this study, Rhinacanthin-C and -D were isolated from Rhinacanthus nasustus, using ethyl acetate, followed by chromatography to isolate Rhinacanthin-C and -D. Both compounds were confirmed using NMR and ultra-performance-LCMS. Using glutamate toxicity in HT-22 cells, we measured cell viability and apoptosis, ROS build-up, and investigated signaling pathways. We show that Rhinacanthin-C and 2-hydroxy-1,4-naphthoquinone have neuroprotective effects against glutamate-induced apoptosis in HT-22 cells. Furthermore, we see that Rhinacanthin-C resulted in autophagy inhibition and increased ER stress. In contrast, low concentrations of Rhinacanthin-C and 2-hydroxy-1,4-naphthoquinone prevented ER stress and CHOP expression. All concentrations of Rhinacanthin-C prevented ROS production and ERK1/2 phosphorylation. We conclude that, while autophagy is present in HT-22 cells subjected to glutamate toxicity, its inhibition is not necessary for cryoprotection.
Full article
(This article belongs to the Special Issue Pharmaceuticals and Cosmeceuticals from Plants: Molecular Pharmacology and Toxicology)
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Open AccessReview
Metformin and Cancer, an Ambiguanidous Relationship
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, , , , and
Pharmaceuticals 2022, 15(5), 626; https://doi.org/10.3390/ph15050626 - 19 May 2022
Abstract
The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2
[...] Read more.
The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.
Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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Open AccessArticle
Spectroscopy Approach for Highly-Efficient Screening of Lectin-Ligand Interactions in Application for Mannose Receptor and Molecular Containers for Antibacterial Drugs
Pharmaceuticals 2022, 15(5), 625; https://doi.org/10.3390/ph15050625 - 19 May 2022
Abstract
Rational search of a ligand for a specific receptor is a cornerstone of a typical drug discovery process. However, to make it more “rational” one would appreciate having detailed information on the functional groups involved in ligand-receptor interaction. Typically, the 3D structure of
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Rational search of a ligand for a specific receptor is a cornerstone of a typical drug discovery process. However, to make it more “rational” one would appreciate having detailed information on the functional groups involved in ligand-receptor interaction. Typically, the 3D structure of a ligand-receptor complex can be built on the basis of time-consuming X-ray crystallography data. Here, a combination of FTIR and fluorescence methods, together with appropriate processing, yields valuable information about the functional groups of both the ligand and receptor involved in the interaction, with the simplicity of conventional spectrophotometry. We have synthesized the “molecular containers” based on cyclodextrins, polyethyleneimines (PEI) or spermine with mannose-rich side-chains of different molecular architecture (reticulated, star-shaped and branched) with variable parameters to facilitate delivery to alveolar macrophages. We have shown that synthetic mannose-rich conjugates are highly affine to the model mannose receptor ConA: Kd ≈ 10−5–10−7 M vs. natural ligand trimannoside (10−5 M). Further, it was shown that molecular containers effectively load levofloxacin (dissociation constants are 5·10−4–5·10−6 M) and the eugenol adjuvant (up to 15–80 drug molecules for each conjugate molecule) by including them in the cyclodextrins cavities, as well as by interacting with polymer chains. Promising formulations of levofloxacin and its enhancer (eugenol) in star-shaped and polymer conjugates of high capacity were obtained. UV spectroscopy demonstrated a doubling of the release time of levofloxacin into the external solution from the complexes with conjugates, and the effective action time (time of 80% release) was increased from 0.5 to 20–70 h. The synergy effect of antibacterial activity of levofloxacin and its adjuvants eugenol and apiol on Escherichia coli was demonstrated: the minimum effective concentration of the antibiotic was approximately halved.
Full article
(This article belongs to the Special Issue Carbohydrate-Based Drugs)
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Open AccessArticle
Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile
by
, , , , , , , , , and
Pharmaceuticals 2022, 15(5), 623; https://doi.org/10.3390/ph15050623 - 19 May 2022
Abstract
The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global
[...] Read more.
The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics.
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(This article belongs to the Special Issue Nitro Group Containing Drugs)
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Open AccessReview
Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects
by
, , , , , , and
Pharmaceuticals 2022, 15(5), 624; https://doi.org/10.3390/ph15050624 - 18 May 2022
Abstract
Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCON 2020. Although various risk factors for lung cancer pathogenesis
[...] Read more.
Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCON 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.
Full article
(This article belongs to the Special Issue Advances in Non-small Cell Lung Cancer Treatment - Current and Future)
Open AccessBrief Report
Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-β and IL-6
by
, , , , , , , , , , , , and
Pharmaceuticals 2022, 15(5), 622; https://doi.org/10.3390/ph15050622 - 18 May 2022
Abstract
During rheumatoid arthritis (RA), the pathogenic role of resident cells within the synovial membrane is suggested, especially for a population frequently referred to as fibroblast-like synoviocytes (FLSs). In this study, we assess the markers of myofibroblast differentiation of RA-FLSs by ex vivo observations
[...] Read more.
During rheumatoid arthritis (RA), the pathogenic role of resident cells within the synovial membrane is suggested, especially for a population frequently referred to as fibroblast-like synoviocytes (FLSs). In this study, we assess the markers of myofibroblast differentiation of RA-FLSs by ex vivo observations and in vitro evaluations following the stimulation with both TGF-β and IL-6. Furthermore, we investigated the possible inhibiting role of tofacitinib, a JAK inhibitor, in this context. Myofibroblast differentiation markers were evaluated on RA synovial tissues by immune-fluorescence or immune-histochemistry. RA-FLSs, stimulated with transforming growth factor (TGF-β) and interleukin-6 (IL-6) with/without tofacitinib, were assessed for myofibroblast differentiation markers expression by qRT-PCR and Western blot. The same markers were evaluated following JAK-1 silencing by siRNA assay. The presence of myofibroblast differentiation markers in RA synovial tissue was significantly higher than healthy controls. Ex vivo, α-SMA was increased, whereas E-Cadherin decreased. In vitro, TGF-β and IL-6 stimulation of RA-FLSs promoted a significant increased mRNA expression of collagen I and α-SMA, whereas E-Cadherin mRNA expression was decreased. In the same conditions, the stimulation with tofacitinib significantly reduced the mRNA expression of collagen I and α-SMA, even if the Western blot did not confirm this finding. JAK-1 gene silencing did not fully prevent the effects of stimulation with TGF-β and IL-6 on these features. TGF-β and IL-6 stimulation may play a role in mediating myofibroblast differentiation from RA-FLSs, promoting collagen I and α-SMA while decreasing E-Cadherin. Following the same stimulation, tofacitinib reduced the increases of both collagen I and α-SMA on RA-FLSs, although further studies are needed to fully evaluate this issue and confirm our results.
Full article
(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations 2022)
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Open AccessArticle
Methylene Blue Is a Nonspecific Protein–Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19
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, , , , , , and
Pharmaceuticals 2022, 15(5), 621; https://doi.org/10.3390/ph15050621 - 18 May 2022
Abstract
We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and for other medical applications as a small-molecule inhibitor of the protein–protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2,
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We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and for other medical applications as a small-molecule inhibitor of the protein–protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concern such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1–5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63–ACE2, hepatitis C virus E–CD81) as well as others (e.g., IL-2–IL-2Rα) with similar potency. This nonspecificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells, both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19.
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(This article belongs to the Special Issue Antiviral Drugs 2021)
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Discovery of Natural Lead Compound from Dendrobium sp. against SARS-CoV-2 Infection
by
, , , , , and
Pharmaceuticals 2022, 15(5), 620; https://doi.org/10.3390/ph15050620 - 18 May 2022
Abstract
Since the pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in December 2019, the infection cases have quickly increased by more than 511 million people. The long epidemic outbreak over 28 months has affected health and economies worldwide. An alternative medicine appears to
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Since the pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in December 2019, the infection cases have quickly increased by more than 511 million people. The long epidemic outbreak over 28 months has affected health and economies worldwide. An alternative medicine appears to be one choice to alleviate symptoms and reduce mortality during drug shortages. Dendrobium extract is one of the traditional medicines used for COVID-19 infection. Several compounds in Dendrobium sp. had been reported to exert pharmacological activities to treat common COVID-19-related symptoms. Herein, in silico screening of 83 compounds from Dendrobium sp. by using the SARS-CoV-2 spike protein receptor-binding domain (RBD) as a drug target was performed in searching for a new lead compound against SARS-CoV-2 infection. Four hit compounds showing good binding affinity were evaluated for antiviral infection activity. The new lead compound DB36, 5-methoxy-7-hydroxy-9,10-dihydro-1,4-phenanthrenequinone, was identified with the IC50 value of 6.87 ± 3.07 µM. The binding mode revealed that DB36 bound with the spike protein at the host receptor, angiotensin-converting enzyme 2 (ACE2) binding motif, resulted in antiviral activity. This study substantiated the use of Dendrobium extract for the treatment of SARS-CoV-2 infection and has identified new potential chemical scaffolds for further drug development of SARS-CoV-2 entry inhibitors.
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(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Inhibition of Human Respiratory Influenza A Virus and Human Betacoronavirus-1 by the Blend of Double-Standardized Extracts of Aronia melanocarpa (Michx.) Elliot and Sambucus nigra L.
by
, , , , , and
Pharmaceuticals 2022, 15(5), 619; https://doi.org/10.3390/ph15050619 - 17 May 2022
Abstract
Viral and bacterial diseases are among the greatest concerns of humankind since ancient times. Despite tremendous pharmacological progress, there is still a need to search for new drugs that could treat or support the healing processes. A rich source of bioactive compounds with
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Viral and bacterial diseases are among the greatest concerns of humankind since ancient times. Despite tremendous pharmacological progress, there is still a need to search for new drugs that could treat or support the healing processes. A rich source of bioactive compounds with antiviral potency include plants such as black chokeberry and elderberry. The aim of this study was to assess the in vitro antiviral ability of an originally designed double-standardized blend of extracts from Aronia melanocarpa (Michx.) Elliot and Sambucus nigra L. (EAM-ESN) or separated extracts of A. melanocarpa (EAM) or S. nigra (ESN) against four human respiratory tract viruses: influenza A virus (A/H1N1), betacoronavirus-1 (HCoV-OC43) belonging to the same β-coronaviruses as the current pandemic SARS-CoV-2, human herpesvirus type 1 (HHV-1), and human adenovirus type 5 (HAdV-5). Antiviral assays (AVAs) were used to evaluate the antiviral activity of the plant extracts in a cell-present environment with extracts tested before, simultaneously, or after viral infection. The virus replication was assessed using the CPE scale or luminescent assay. The EAM-ESN blend strongly inhibited A/H1N1 replication as well as HCoV-OC43, while having a limited effect against HHV-1 and HAdV-5. This activity likely depends mostly on the presence of the extract of S. nigra. However, the EAM-ESN blend possesses more effective inhibitory activity toward virus replication than its constituent extracts. A post-infection mechanism of action of the EAM-ESN make this blend the most relevant for potential drugs and supportive treatments; thus, the EAM-ESN blend might be considered as a natural remedy in mild, seasonal respiratory viral infections.
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(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)
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Integrin/TGF-β1 Inhibitor GLPG-0187 Blocks SARS-CoV-2 Delta and Omicron Pseudovirus Infection of Airway Epithelial Cells In Vitro, Which Could Attenuate Disease Severity
by
, , , , and
Pharmaceuticals 2022, 15(5), 618; https://doi.org/10.3390/ph15050618 - 17 May 2022
Abstract
As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with
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As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate the blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced the inhibition of pseudovirus infection by GLPG-0187. Because integrins activate transforming growth factor beta (TGF-β) signaling, we compared the plasma levels of active and total TGF-β in COVID-19+ patients. The plasma TGF-β1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. Moreover, the inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and it may mitigate COVID-19 severity through decreased TGF-β1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.
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(This article belongs to the Topic Compounds with Medicinal Value)
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Tilorone and Cridanimod Protect Mice and Show Antiviral Activity in Rats despite Absence of the Interferon-Inducing Effect in Rats
by
, , , , , and
Pharmaceuticals 2022, 15(5), 617; https://doi.org/10.3390/ph15050617 - 17 May 2022
Abstract
The synthetic compounds, Tilorone and Cridanimod, have the antiviral activity which initially had been ascribed to the capacity to induce interferon. Both drugs induce interferon in mice but not in humans. This study investigates whether these compounds have the antiviral activity in mice
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The synthetic compounds, Tilorone and Cridanimod, have the antiviral activity which initially had been ascribed to the capacity to induce interferon. Both drugs induce interferon in mice but not in humans. This study investigates whether these compounds have the antiviral activity in mice and rats since rats more closely resemble the human response. Viral-infection models were created in CD-1 mice and Wistar rats. Three strains of Venezuelan equine encephalitis virus were tested for the performance in these models. One virus strain is the molecularly cloned attenuated vaccine. The second strain has major virulence determinants converted to the wild-type state which are present in virulent strains. The third virus has wild-type virulence determinants, and in addition, is engineered to express green fluorescent protein. Experimentally infected animals received Tilorone or Cridanimod, and their treatment was equivalent to the pharmacopoeia-recomended human treatment regimen. Tilorone and Cridanimod show the antiviral activity in mice and rats and protect the mice from death. In rats, both drugs diminish the viremia. These drugs do not induce interferon-alpha or interferon-beta in rats. The presented observations allow postulating the existence of an interferon-independent and species-independent mechanism of action.
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(This article belongs to the Section Pharmacology)
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Immunosuppressant Therapies in COVID-19: Is the TNF Axis an Alternative?
Pharmaceuticals 2022, 15(5), 616; https://doi.org/10.3390/ph15050616 - 17 May 2022
Abstract
The study of cytokine storm in COVID-19 has been having different edges in accordance with the knowledge of the disease. Various cytokines have been the focus, especially to define specific treatments; however, there are no conclusive results that fully support any of the
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The study of cytokine storm in COVID-19 has been having different edges in accordance with the knowledge of the disease. Various cytokines have been the focus, especially to define specific treatments; however, there are no conclusive results that fully support any of the options proposed for emergency treatment. One of the cytokines that requires a more exhaustive review is the tumor necrosis factor (TNF) and its receptors (TNFRs) as increased values of soluble formats for both TNFR1 and TNFR2 have been identified. TNF is a versatile cytokine with different impacts at the cellular level depending on the action form (transmembrane or soluble) and the receptor to which it is associated. In that sense, the triggered mechanisms can be diversified. Furthermore, there is the possibility of the joint action provided by synergism between one or more cytokines with TNF, where the detonation of combined cellular processes has been suggested. This review aims to discuss some roles of TNF and its receptors in the pro-inflammatory stage of COVID-19, understand its ways of action, and let to reposition this cytokine or some of its receptors as therapeutic targets.
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(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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