scholarly journals N-Heterocyclic Carbene Platinum(IV) as Metallodrug Candidates: Synthesis and 195Pt NMR Chemical Shift Trend

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3148
Author(s):  
Mathilde Bouché ◽  
Bruno Vincent ◽  
Thierry Achard ◽  
Stéphane Bellemin-Laponnaz
Keyword(s):  
Chemical Shift ◽  
Structural Changes ◽  
Structural Variations ◽  
Electronic Density ◽  
Ic50 Values ◽  
In Trans ◽  
The Impact ◽  
Micromolar Range ◽  
Amine Ligand

A series of octahedral platinum(IV) complexes functionalized with both N-heterocyclic carbene (NHC) ligands were synthesized according to a straightforward procedure and characterized. The coordination sphere around the metal was varied, investigating the influence of the substituted NHC and the amine ligand in trans position to the NHC. The influence of those structural variations on the chemical shift of the platinum center were evaluated by 195Pt NMR. This spectroscopy provided more insights on the impact of the structural changes on the electronic density at the platinum center. Investigation of the in vitro cytotoxicities of representative complexes were carried on three cancer cell lines and showed IC50 values down to the low micromolar range that compare favorably with the benchmark cisplatin or their platinum(II) counterparts bearing NHC ligands.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

Micro-Structural Stability of Micropropagated Plants of Vitex negundo L.

2021 ◽  
pp. 1-9
Author(s):  
M. Manokari ◽  
S. Priyadharshini ◽  
Mahipal S. Shekhawat
Keyword(s):  
Structural Changes ◽  
Growth Conditions ◽  
Culture Industry ◽  
Vascular Bundles ◽  
Vitex Negundo ◽  
Structural Variations ◽  
Structural Repair ◽  
Micropropagated Plants ◽  
Palisade Cells

Abstract Micropropagation techniques allow producing large numbers of clones of genetically identical plants. However, there is evidence of disorders in internal structures due to sophisticated in vitro conditions. Such variations are responsible for the mortality of plantlets in the field and cause huge loss to the tissue culture industry. Anatomical evaluation at different growth conditions allows for understanding structural repair of in vitro raised plantlets. Therefore, the present study was aimed to identify the structural changes that occurred in micropropagated plants of Vitex negundo under heterotrophic, photomixotrophic, and photoautotrophic conditions. To achieve this, structural variations were analyzed in the plantlets obtained from in vitro, greenhouse and field transferred stages using light microscopy. Underdeveloped dermal tissues, palisade cells, intercellular spaces, mechanical tissues, vascular bundles, and ground tissues were observed with the plants growing under in vitro conditions. The self-repairing of structural disorders and transitions in vegetative anatomy was observed during hardening under the greenhouse environment. Field transferred plantlets were characterized by well-developed internal anatomy. These findings showed that the micropropagated plantlets of V. negundo were well-adapted through a series of self-repairing the in vitro induced structural abnormalities at the subsequent stages of plant development.

scholarly journals Molecular insights into the inhibition of plasmepsins by HIV-1 protease inhibitors: Implications for antimalarial drug discovery

2021 ◽  
Author(s):  
Vandana Mishra ◽  
Ishan Rathore ◽  
Anuradha Deshmukh ◽  
Swati Patankar ◽  
Alla Gustchina ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Drug Targets ◽  
Drug Repurposing ◽  
Binding Mode ◽  
Ic50 Values ◽  
Multiple Regions ◽  
Potential Drug Targets ◽  
Hiv 1 ◽  
Micromolar Range

Malaria is a deadly disease, and the worldwide emergence of drug resistance in the Plasmodium parasites demands the development of novel and potent antimalarials. HIV-1 protease inhibitors (HIV-1 PIs) alleviate the Plasmodium pathogenesis during malaria/HIV-1 co-infection plausibly by inhibiting vacuolar plasmepsins (PMs), the hemoglobin degrading proteases from P. falciparum. All five FDA-approved HIV-1 PIs tested against PMII exhibit the Ki values in the low micromolar range of which RTV and LPV display the highest inhibition activity. Both inhibitors impede in vitro growth of P. falciparum at low micromolar IC50 values. We report the first crystal structures of PMII complexed with RTV and LPV that reveal the binding mode and interactions of the inhibitors in the active site as well as elucidate the mechanism underlying their differential potency. The conformational flexibility of the P4 group in RTV allows it to explore multiple regions of the S4 pocket. The present study establishes vacuolar PMs as potential drug targets of HIV-1 PIs. The molecular details explaining the inhibitory mechanism of HIV-1 PIs might be crucial in designing novel and potent antimalarial analogs. This work strengthens the prospect of drug repurposing as an alternative strategy towards antimalarial treatments and provides an opportunity to tackle malaria and HIV-1 co-infection.

scholarly journals Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations

2020 ◽  
Author(s):  
Ming-Huei Chen ◽  
Laura M. Raffield ◽  
Abdou Mousas ◽  
Saori Sakaue ◽  
Jennifer E. Huffman ◽  
...  
Keyword(s):  
South Asians ◽  
Missense Variant ◽  
European Ancestry ◽  
Credible Sets ◽  
Global Representation ◽  
In Trans ◽  
Meta Analyses ◽  
The Impact

SUMMARYMost loci identified by GWAS have been found in populations of European ancestry (EA). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EA individuals, we identified 5,552 trait-variant associations at P<5×10−9, including 71 novel loci not found in EA populations. We also identified novel ancestry-specific variants not found in EA, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional, and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EA-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations, and compared genetic architecture and the impact of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

scholarly journals Antioxidants Bioaccessibility and Lactobacillus salivarius (CECT 4063) Survival Following the In Vitro Digestion of Vacuum Impregnated Apple Slices: Effect of the Drying Technique, the Addition of Trehalose, and High-Pressure Homogenization

Foods ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2155
Author(s):  
Cristina Gabriela Burca-Busaga ◽  
Noelia Betoret ◽  
Lucía Seguí ◽  
Jorge García-Hernández ◽  
Manuel Hernández ◽  
...  
Keyword(s):  
Freeze Drying ◽  
Structural Changes ◽  
In Vitro Digestion ◽  
Food Matrix ◽  
Lactobacillus Salivarius ◽  
Gastrointestinal Conditions ◽  
Apple Slices ◽  
Maximum Protection ◽  
The Impact

To benefit the health of consumers, bioactive compounds must reach an adequate concentration at the end of the digestive process. This involves both an effective release from the food matrix where they are contained and a high resistance to exposure to gastrointestinal conditions. Accordingly, this study evaluates the impact of trehalose addition (10% w/w) and homogenization (100 MPa), together with the structural changes induced in vacuum impregnated apple slices (VI) by air-drying (AD) and freeze-drying (FD), on Lactobacillus salivarius spp. salivarius (CECT 4063) survival and the bioaccessibility of antioxidants during in vitro digestion. Vacuum impregnated apple slices conferred maximum protection to the lactobacillus strain during its passage through the gastrointestinal tract, whereas drying with air reduced the final content of the living cells to values below 10 cfu/g. The bioaccessibility of antioxidants also reached the highest values in the VI samples, in which the release of both the total phenols and total flavonoids to the liquid phase increased with in vitro digestion. The addition of trehalose and homogenization at 100 MPa increased the total bioaccessibility of antioxidants in FD and AD apples and the total bioaccessibility of flavonoids in the VI samples. Homogenizing at 100 MPa also increased the survival of L. salivarius during in vitro digestion in FD samples.

scholarly journals The Effect of Blanching on Phytochemical Content and Bioactivity of Hypochaeris and Hyoseris Species (Asteraceae), Vegetables Traditionally Used in Southern Italy

Foods ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 32
Author(s):  
Vincenzo Sicari ◽  
Monica R. Loizzo ◽  
Ana Sanches Silva ◽  
Rosa Romeo ◽  
Giovanni Spampinato ◽  
...  
Keyword(s):  
Health Effect ◽  
Wild Plants ◽  
In Vitro Tests ◽  
Plant Materials ◽  
Phytochemical Content ◽  
Chlorophyll Contents ◽  
Reducing Ability ◽  
Ic50 Values ◽  
The Impact

The impact of blanching on the phytochemical content and bioactivity of Hypochaeris laevigata (HL), Hypochaeris radicata (HR), Hyoseris radiata (HRA), and Hyoseris lucida subsp. taurina (HT) leaves was studied and compared to fresh plant materials and residual blanching water. For this purpose, total phenols, flavonoids, carotenoids, and chlorophyll contents were quantified. The antioxidant effect was investigated by using different in vitro tests (β-carotene, ferric reducing ability power (FRAP), 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH), whereas the potential inhibitory activity of key enzymes linked to obesity was screened against lipase, α-amylase, and α-glucosidase. Generally, the phytochemical content followed the trend: fresh > blanching water > blanched samples. The same trend was observed in the antioxidant activity independently of the applied test as well as in the inhibition of lipase and carbohydrates-hydrolysing enzymes. In particular, fresh Hypochaeris laevigata (HL1) showed the lowest inhibitory concentration 50% (IC50) values of 31.3 and 42.7 μg/mL, against α-glucosidase and α-amylase, respectively, whereas fresh Hyoseris radiata (HRA1) showed the most promising hypolipidemic activity (IC50 value of 39.8 μg/mL). Collectively, these results support the health effect of these wild plants and demonstrated that blanching water should be reused in food preparation since it is a good source of bioactive compounds and its consumption should be recommended in order to increase the uptake of micronutrients.

scholarly journals Novel hybrids of oxoisoaporphine-tryptamine as acetylcholinesterase-induced β-amyloid aggregation inhibitors with improved antioxidant properties

2015 ◽  
Vol 80 (2) ◽  
pp. 127-136 ◽  
Author(s):  
Hai-Tao Zhao ◽  
Shu-Ming Zhong ◽  
Jiang-Ke Qin ◽  
Huang Tang
Keyword(s):  
Inhibitory Activity ◽  
Antioxidant Properties ◽  
Drug Candidates ◽  
Ache Inhibitors ◽  
Ache Inhibitory Activity ◽  
Ic50 Values ◽  
Aggregation Inhibitors ◽  
Β Amyloid ◽  
Micromolar Range

A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their antioxidant ability and inhibitory potency on AChE and AChE-induced b-amyloid (Ab) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tryptamine or its derivative, connected through a a,w - alkyldiamide bridge. These hybrids exhibit moderate AChE inhibitory activity with IC50 values in the micromolar range and significant in vitro inhibitory activity toward the AChE-induced Ab aggregation. Moreover, six out of the nine hybrids of this series exhibit a higher oxygen radical absorbance capacity than trolox, which makes them promising anti-Alzheimer drug candidates.

scholarly journals Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease

2021 ◽  
Vol 478 (13) ◽  
pp. 2499-2515 ◽  
Author(s):  
Jennifer C. Milligan ◽  
Theresa U. Zeisner ◽  
George Papageorgiou ◽  
Dhira Joshi ◽  
Christelle Soudy ◽  
...  
Keyword(s):  
Economic Effects ◽  
Calpain Inhibitor ◽  
Chemical Library ◽  
Antiviral Compounds ◽  
Main Protease ◽  
The World ◽  
Ic50 Values ◽  
Global Population ◽  
Micromolar Range

The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.

scholarly journals A trapped double bond-photoisomerization intermediate in a bacterial photoreceptor

2017 ◽  
Author(s):  
Xiuling Xu ◽  
Astrid Höppner ◽  
Kai-Hong Zhao ◽  
Wolfgang Gärtner
Keyword(s):  
Double Bond ◽  
Conformational Changes ◽  
Structural Changes ◽  
Color Change ◽  
Protein Domain ◽  
Tryptophan Residue ◽  
Intermediate Structure ◽  
The Impact

AbbreviationsASUasymmetric unitBV, PCB, PVB (bilin compounds serving as chromophores)biliverdin Ixα, phycocyanobilin, phycoviolobilinCAPSON-cyclohexyl-2-hydroxyl-3-aminopropanesulfonic acidCBCRcyanobacteriochromeGAF (protein domain)cGMP-specific phosphodiesterases adenylyl cyclases and FhlAIMACimmobilized metal-affinity chromatographyMRmolecular replacementPAS (protein domain)Per-Arnt-SimPHY (protein domain)phytochrome-specificPfr, Pg, Prfar red-, green-, and red-absorbing states of phytochromes and CBCRsSummaryThe GAF3 domain of cyanobacteriochrome Slr1393 (Synechocystis PCC6803) with an in vivo assembled phycocyanobilin (PCB) chromophore has been crystallized in parental state (1.8 Å) and photoproduct state (1.86 Å), identified by 15-Z and 15-E chromophore configuration. Comparison of both structures for the same protein allows precise determination of structural changes after photo-activation. The chromophore photoisomerization causes an outward movement and partial helix formation of a formerly unstructured loop. A tryptophan residue located in this loop, in π-π stacking distance to PCB in the dark state, moves away by 14 Å opening the binding cleft for the entry of water molecules. Also the in vitro assembled protein (chromophore addition to apo-protein) has been crystallized (1.6 Å resolution). Most importantly, an intermediate structure was solved (2.1 Å) with the protein in photoproduct conformation and the chromophore already isomerized into the parental 15-Z configuration, thereby giving insight into chromophore-initiated conformational protein changes.Impact StatementThis manuscript presents crystal structures of a photochromic protein in both states, before (1.6 Å) and after (1.9 Å) the light induced photochemical event with sufficient resolution to allow detailed description of conformational changes of chromophore and protein. The light driven reaction, double bond photoisomerization of a covalently bound bilin chromophore is presented here for the first time. Our results allow determining the impact of the chromophore photochemistry on the protein conformation. In addition, we succeeded in trapping an intermediate carrying the chromophore already in isomerized state with the protein still in unchanged conformation. Absorption spectra of this intermediate clearly demonstrate a color change, thus allowing conclusion that the absorption of phytochromes is predominantly determined by the chromophore conformation alone with only moderate effect of the surrounding protein.Authors’ ContributionsXX, KHZ, and WG designed the experiment. XX generated the protein. AH performed crystallization trials, collected the X-ray diffraction data and solved the structure. All authors contributed in preparing the manuscript.

scholarly journals Investigation of Lupeol as Anti-Melanoma Agent: An In Vitro-In Ovo Perspective

2021 ◽  
Vol 28 (6) ◽  
pp. 5054-5066
Author(s):  
Flavia Bociort ◽  
Ioana Gabriela Macasoi ◽  
Iasmina Marcovici ◽  
Andrei Motoc ◽  
Cristina Grosu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Anticancer Effect ◽  
In Ovo ◽  
Antiangiogenic Effect ◽  
Ic50 Values ◽  
Life Threatening ◽  
And Migration ◽  
Disease Stages ◽  
The Impact

Malignant melanoma (MM) represents the most life-threatening skin cancer worldwide, with a narrow and inefficient chemotherapeutic arsenal available in advanced disease stages. Lupeol (LUP) is a triterpenoid-type phytochemical possessing a broad spectrum of pharmacological properties, including a potent anticancer effect against several neoplasms (e.g., colorectal, lung, and liver). However, its potential as an anti-melanoma agent has been investigated to a lesser extent. The current study focused on exploring the impact of LUP against two human MM cell lines (A375 and RPMI-7951) in terms of cell viability, confluence, morphology, cytoskeletal distribution, nuclear aspect, and migration. Additionally, the in ovo antiangiogenic effect has been also examined. The in vitro results indicated concentration-dependent and selective cytotoxicity against both MM cell lines, with estimated IC50 values of 66.59 ± 2.20 for A375, and 45.54 ± 1.48 for RPMI-7951, respectively, accompanied by a reduced cell confluence, apoptosis-specific nuclear features, reorganization of cytoskeletal components, and inhibited cell migration. In ovo, LUP interfered with the process of angiogenesis by reducing the formation of neovascularization. Despite the potential anti-melanoma effect illustrated in our in vitro-in ovo study, further investigations are required to elucidate the underlying LUP-induced effects in A375 and RPMI-7951 MM cells.

Sign in / Sign up

Export Citation Format

Share Document