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1.
Chem Commun (Camb) ; 57(93): 12476-12479, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1500757

ABSTRACT

We identified small-molecule enhancers of cellular stress granules by observing molecular crowding of proteins and RNAs in a time-dependent manner. Hit molecules sensitized the IRF3-mediated antiviral mechanism in the presence of poly(I:C) and inhibited the replication of SARS-CoV-2 by inducing stress granule formation. Thus, modulating multimolecular crowding can be a promising strategy against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Benzopyrans/pharmacology , Cytoplasmic Granules/drug effects , Pyrazoles/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Benzopyrans/chemistry , Cell Line, Tumor , Chlorocebus aethiops , Cytoplasmic Granules/metabolism , Dose-Response Relationship, Drug , Drug Combinations , Humans , Interferon Regulatory Factor-3/metabolism , Lopinavir/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Poly I-C/pharmacology , Pyrazoles/chemistry , Structure-Activity Relationship , Vero Cells
2.
Mar Drugs ; 19(10)2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1480860

ABSTRACT

To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae Grateloupia sp. Two new azaphilones, 8a-epi-hypocrellone A (1), 8a-epi-eupenicilazaphilone C (2), together with five known azaphilones, hypocrellone A (3), eupenicilazaphilone C (4), ((1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde (5), sclerotiorin (6), and isochromophilone IV (7) were isolated from the alga-derived fungus Penicillium sclerotiorum. The structures of isolated azaphilones (1-7) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound 1 showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 µM of compounds 1, 3, and 7 inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds 2 and 6 respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-ß.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Microalgae , Penicillium , Pigments, Biological/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Aquatic Organisms , Benzopyrans/chemistry , Benzopyrans/therapeutic use , Cell Line, Tumor/drug effects , Fibroblasts/drug effects , Functional Food , Neuroblastoma/drug therapy , Pigments, Biological/chemistry , Pigments, Biological/therapeutic use , Structure-Activity Relationship
3.
Antiviral Res ; 190: 105075, 2021 06.
Article in English | MEDLINE | ID: covidwho-1290345

ABSTRACT

The emerging SARS-CoV-2 infection is the cause of the global COVID-19 pandemic. To date, there are limited therapeutic options available to fight this disease. Here we examined the inhibitory abilities of two broad-spectrum antiviral natural products chebulagic acid (CHLA) and punicalagin (PUG) against SARS-CoV-2 viral replication. Both CHLA and PUG reduced virus-induced plaque formation in Vero-E6 monolayer at noncytotoxic concentrations, by targeting the enzymatic activity of viral 3-chymotrypsin-like cysteine protease (3CLpro) as allosteric regulators. Our study demonstrates the potential use of CHLA and PUG as novel COVID-19 therapies.


Subject(s)
Antiviral Agents/pharmacology , Benzopyrans/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Glucosides/pharmacology , Hydrolyzable Tannins/pharmacology , SARS-CoV-2/drug effects , Allosteric Site , Animals , Antiviral Agents/chemistry , Benzopyrans/chemistry , COVID-19/drug therapy , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Discovery , Glucosides/chemistry , Molecular Docking Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2/metabolism , Vero Cells , Virus Replication/drug effects
4.
Molecules ; 26(13)2021 Jun 28.
Article in English | MEDLINE | ID: covidwho-1287270

ABSTRACT

The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess antiparasitic activity towards Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, which are protozoa responsible for Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SARs studies, based on the pulchrol scaffold, showed which effects exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent than pulchrol and the current drugs used to treat leishmaniasis and Chagas disease (miltefosine and benznidazole, respectively), in vitro. Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro towards T. cruzi epimastigotes, L. braziliensis promastigotes, and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parental compound pulchrol, and in some cases even benznidazole and miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which indeed was shown to be potent towards all the parasites.


Subject(s)
Benzopyrans , Leishmania braziliensis/growth & development , Trypanocidal Agents , Trypanosoma cruzi/growth & development , Benzopyrans/chemistry , Benzopyrans/pharmacology , Chagas Disease/drug therapy , Humans , Leishmaniasis, Cutaneous/drug therapy , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology
5.
BMC Complement Med Ther ; 21(1): 41, 2021 Jan 21.
Article in English | MEDLINE | ID: covidwho-1041078

ABSTRACT

BACKGROUND: The latest coronavirus SARS-CoV-2, discovered in China and rapidly spread Worldwide. COVID-19 affected millions of people and killed hundreds of thousands worldwide. There are many ongoing studies investigating drug(s) suitable for preventing and/or treating this pandemic; however, there are no specific drugs or vaccines available to treat or prevent SARS-CoV-2 as of today. METHODS: Fifty-eight fragrance materials, which are classified as allergen fragrance molecules, were selected and used in this study. Docking simulations were carried out using four functional proteins; the Covid19 Main Protase (MPro), Receptor binding domain (RBD) of spike protein, Nucleocapsid, and host Bromodomain protein (BRD2), as target macromolecules. Three different software, AutoDock, AutoDock Vina (Vina), and Molegro Virtual Docker (MVD), running a total of four different docking protocol with optimized energy functions were used. Results were compared with the five molecules reported in the literature as potential drugs against COVID-19. Virtual screening was carried out using Vina, molecules satisfying our cut-off (- 6.5 kcal/mol) binding affinity was confirmed by MVD. Selected molecules were analyzed using the flexible docking protocol of Vina and AutoDock default settings. RESULTS: Ten out of 58 allergen fragrance molecules were selected for further docking studies. MPro and BRD2 are potential targets for the tested allergen fragrance molecules, while RBD and Nucleocapsid showed weak binding energies. According to AutoDock results, three molecules, Benzyl Cinnamate, Dihydroambrettolide, and Galaxolide, had good binding affinities to BRD2. While Dihydroambrettolide and Galaxolide showed the potential to bind to MPro, Sclareol and Vertofix had the best calculated binding affinities to this target. When the flexible docking results analyzed, all the molecules tested had better calculated binding affinities as expected. Benzyl Benzoate and Benzyl Salicylate showed good binding affinities to BRD2. In the case of MPro, Sclareol had the lowest binding affinity among all the tested allergen fragrance molecules. CONCLUSION: Allergen fragrance molecules are readily available, cost-efficient, and shown to be safe for human use. Results showed that several of these molecules had comparable binding affinities as the potential drug molecules reported in the literature to target proteins. Thus, these allergen molecules at correct doses could have significant health benefits.


Subject(s)
Allergens/chemistry , Allergens/immunology , COVID-19/drug therapy , COVID-19/immunology , Odorants , Perfume/chemistry , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Allergens/administration & dosage , Allergens/therapeutic use , Benzopyrans/chemistry , Benzopyrans/metabolism , Benzyl Compounds/chemistry , Benzyl Compounds/metabolism , Cinnamates/chemistry , Cinnamates/metabolism , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/metabolism , Diterpenes/chemistry , Diterpenes/metabolism , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Docking Simulation , Perfume/administration & dosage , Perfume/therapeutic use , Phosphoproteins/chemistry , Phosphoproteins/metabolism , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Transcription Factors/chemistry , Transcription Factors/metabolism
6.
Bioorg Med Chem ; 28(4): 115273, 2020 02 15.
Article in English | MEDLINE | ID: covidwho-833276

ABSTRACT

An octahydroisochromene scaffold has been introduced into a known SARS 3CL protease inhibitor as a novel hydrophobic core to interact with the S2 pocket of the protease. An alkyl or aryl substituent was also introduced at the 1-position of the octahydroisochromene scaffold and expected to introduce additional interactions with the protease. Sharpless-Katsuki asymmetric epoxidation and Sharpless asymmetric dihydroxylation were employed to construct the octahydroisochromene scaffold. The introductions of the P1 site His-al and the substituent at 1-position was achieved using successive reductive amination reactions. Our initial evaluations of the diastereo-isomeric mixtures (16a-d) revealed that the octahydroisochromene moiety functions as a core hydrophobic scaffold for the S2 pocket of the protease and the substituent at the 1-position may form additional interactions with the protease. The inhibitory activities of the diastereoisomerically-pure inhibitors (3a-d) strongly suggest that a specific stereo-isomer of the octahydroisochromene scaffold, (1S, 3S) 3b, directs the P1 site imidazole, the warhead aldehyde, and substituent at the 1-position of the fused ring to their appropriate pockets in the protease.


Subject(s)
Benzopyrans/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS Virus/enzymology , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Coronavirus 3C Proteases/metabolism , Dose-Response Relationship, Drug , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Structure-Activity Relationship
7.
J Mol Graph Model ; 100: 107690, 2020 11.
Article in English | MEDLINE | ID: covidwho-670741

ABSTRACT

Coronavirus epidemic 2019 (COVID-19), caused by novel coronavirus (2019-nCoV), is newly increasing worldwide and elevating global health concerns. Similar to SARS-CoV and MERS-CoV, the viral key 3-chymotrypsin-like cysteine protease enzyme (3CLPro), which controls 2019-nCoV duplications and manages its life cycle, could be pointed as a drug discovery target. Herein, we theoretically studied the binding ability of 10 structurally different anthocyanins with the catalytic dyad residues of 3CLpro of 2019-nCoV using molecular docking modelling. The results revealed that the polyacylated anthocyanins, including phacelianin, gentiodelphin, cyanodelphin, and tecophilin, were found to authentically bind with the receptor binding site and catalytic dyad (Cys145 and His41) of 2019-nCoV-3CLpro. Our analyses revealed that the top four hits might serve as potential anti-2019-nCoV leading molecules for further optimization and drug development process to combat COVID-19. This study unleashed that anthocyanins with specific structure could be used as effective anti-COVID-19 natural components.


Subject(s)
Anthocyanins/chemistry , Antiviral Agents/chemistry , Benzopyrans/chemistry , Betacoronavirus/chemistry , Cysteine Endopeptidases/chemistry , Glucosides/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/chemistry , Amino Acid Sequence , Betacoronavirus/enzymology , Binding Sites , Coronavirus 3C Proteases , Molecular Docking Simulation , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , SARS-CoV-2 , Sequence Alignment , Structure-Activity Relationship , Thermodynamics , Viral Nonstructural Proteins/antagonists & inhibitors
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