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1.
Eur J Med Chem ; 229: 114046, 2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1768050

ABSTRACT

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Animals , Drug Design , High-Throughput Screening Assays , Humans , Virus Replication/drug effects
2.
Molecules ; 27(4)2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1715566

ABSTRACT

Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. In this study, a series of hexa-, hepta- and octavalent BA derivatives based on α-, ß- and γ-cyclodextrin scaffolds, respectively, with varying lengths of flexible oligo(ethylene glycol) linkers was designed and synthesized using a microwave-assisted copper-catalyzed 1,3-dipolar cycloaddition reaction. The generated BA-cyclodextrin conjugates were tested for their in vitro activity against influenza A/WSN/33 (H1N1) virus and cytotoxicity. Among the tested compounds, 58, 80 and 82 showed slight cytotoxicity to Madin-Darby canine kidney cells with viabilities ranging from 64 to 68% at a high concentration of 100 µM. Four conjugates 51 and 69-71 showed significant inhibitory effects on influenza infection with half maximal inhibitory concentration values of 5.20, 9.82, 7.48 and 7.59 µM, respectively. The structure-activity relationships of multivalent BA-cyclodextrin conjugates were discussed, highlighting that multivalent BA derivatives may be potential antiviral agents against influenza infection.


Subject(s)
Antiviral Agents , Cyclodextrins/chemistry , Influenza A Virus, H1N1 Subtype/metabolism , Orthomyxoviridae Infections/drug therapy , Pentacyclic Triterpenes/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Dogs , Drug Evaluation, Preclinical , Madin Darby Canine Kidney Cells , Orthomyxoviridae Infections/metabolism , Structure-Activity Relationship
3.
Sci Rep ; 12(1): 3341, 2022 02 28.
Article in English | MEDLINE | ID: covidwho-1713213

ABSTRACT

This study reports the synthesis of hybrid nanostructures composed of cerium dioxide and microcrystalline cellulose prepared by the microwave-assisted hydrothermal route under distinct temperature and pH values. Their structural, morphological and spectroscopic behaviors were investigated by X-Rays Diffraction, Field Emission Gun Scanning Electron Microscopy, High-Resolution Transmission Electron Microscopy, and Fourier-Transform Infrared, Ultraviolet-Visible, Raman and Positron Annihilation Lifetime spectroscopies to evaluate the presence of structural defects and their correlation with the underlying mechanism regarding the biocide activity of the studied material. The samples showed mean crystallite sizes around 10 nm, characterizing the formation of quantum dots unevenly distributed along the cellulose surface with a certain agglomeration degree. The samples presented the characteristic Ce-O vibration close to 450 cm-1 and a second-order mode around 1050 cm-1, which is indicative of distribution of localized energetic levels originated from defective species, essential in the scavenging of reactive oxygen species. Positron spectroscopic studies showed first and second lifetime components ranging between 202-223 ps and 360-373 ps, respectively, revealing the presence of two distinct defective oxygen species, in addition to an increment in the concentration of Ce3+-oxygen vacancy associates as a function of temperature. Therefore, we have successfully synthesized hybrid nanoceria structures with potential multifunctional therapeutic properties to be further evaluated against the COVID-19.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , Cerium/chemistry , Nanostructures/chemistry , SARS-CoV-2/chemistry , Antiviral Agents/therapeutic use , Humans
4.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1705973

ABSTRACT

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects
5.
Chem Commun (Camb) ; 58(11): 1804-1807, 2022 Feb 03.
Article in English | MEDLINE | ID: covidwho-1639537

ABSTRACT

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC50 of 190 nM and neutralizes the authentic SARS-CoV-2 in Caco2 cells with an IC50 of 2.4 µM. Our study should provide a new insight for the optimization of peptide-based anti-SARS-CoV-2 inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Peptide Fragments/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Cell Line, Tumor , Humans , Microbial Sensitivity Tests , Peptide Fragments/chemical synthesis , Peptide Fragments/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
6.
Molecules ; 27(2)2022 Jan 17.
Article in English | MEDLINE | ID: covidwho-1635108

ABSTRACT

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2' or C3' is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2' was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Carbon/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Nucleotides/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/enzymology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Nucleotides/chemical synthesis , Nucleotides/chemistry , SARS-CoV-2/drug effects , Stereoisomerism
7.
Molecules ; 27(2)2022 Jan 13.
Article in English | MEDLINE | ID: covidwho-1624914

ABSTRACT

A novel series of 1-aryl-N-[4-phenyl-5-(arylazo)thiazol-2-yl)methanimines has been synthesized via the condensation of 2-amino-4-phenyl-5-arylazothiazole with various aromatic aldehydes. The synthesized imines were characterized by spectroscopic techniques, namely 1H and 13C-NMR, FTIR, MS, and Elemental Analysis. A molecular comparative docking study for 3a-f was calculated, with reference to two approved drugs, Molnupiravir and Remdesivir, using 7BQY (Mpro; PDB code 7BQY; resolution: 1.7 A°) under identical conditions. The binding scores against 7BQY were in the range of -7.7 to -8.7 kcal/mol for 3a-f. The high scores of the compounds indicated an enhanced binding affinity of the molecules to the receptor. This is due to the hydrophobic interactions and multi-hydrogen bonds between 3a-f ligands and the receptor's active amino acid residues. The main aim of using in silco molecular docking was to rank 3a-f with respect to the approved drugs, Molnupiravir and Remdesivir, using free energy methods as greener pastures. A further interesting comparison presented the laydown of the ligands before and after molecular docking. These results and other supporting statistical analyses suggested that ligands 3a-f deserve further investigation in the context of potential therapeutic agents for COVID-19. Free-cost, PASS, SwissADME, and Way2drug were used in this research paper to determine the possible biological activities and cytotoxicity of 3a-f.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , Imines/chemistry , Thiazoles/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Alanine/analogs & derivatives , Alanine/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Computer Simulation , Coronavirus 3C Proteases/chemistry , Cytidine/analogs & derivatives , Cytidine/chemistry , Hydroxylamines/chemistry , Imines/chemical synthesis , Imines/pharmacokinetics , Imines/toxicity , Molecular Docking Simulation , SARS-CoV-2/drug effects , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Thiazoles/toxicity
8.
J Med Chem ; 64(24): 18010-18024, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1616926

ABSTRACT

Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.


Subject(s)
Antiviral Agents/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Imino Sugars/pharmacology , Inositol/analogs & derivatives , alpha-Glucosidases/metabolism , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Binding Sites , Chlorocebus aethiops , Crystallography, X-Ray , Dengue Virus/drug effects , Endoplasmic Reticulum/enzymology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/metabolism , Humans , Imino Sugars/chemical synthesis , Imino Sugars/metabolism , Inositol/chemical synthesis , Inositol/metabolism , Inositol/pharmacology , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/drug effects , Vero Cells , alpha-Glucosidases/chemistry
9.
Molecules ; 27(1)2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1613911

ABSTRACT

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502-8 µM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9-27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , SARS-CoV-2/drug effects , Virus Replication , Animals , Antiviral Agents/chemical synthesis , COVID-19/virology , Chlorocebus aethiops , HIV Infections/virology , HeLa Cells , Humans , In Vitro Techniques , Vero Cells
10.
Int J Mol Sci ; 23(1)2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1613825

ABSTRACT

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.


Subject(s)
Antiviral Agents/chemical synthesis , Cellulose/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Nucleosides/chemical synthesis , SARS-CoV-2/enzymology , Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacokinetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacokinetics , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacokinetics , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Computational Biology , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Nucleosides/chemistry , Nucleosides/pharmacokinetics , Pyrolysis , SARS-CoV-2/drug effects
11.
Emerg Microbes Infect ; 11(1): 208-211, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1598042

ABSTRACT

We performed an annotation of 35 mutations in the spike protein of the SARS-CoV-2 Omicron variant. Our analysis of the mutations indicates that Omicron has gained prominent immune evasion and potential for enhanced transmissibility. Previous modeling study has revealed that continued evolution in both immune evasion and enhanced transmissibility by SARS-CoV-2 would compromise vaccines as tools for the pandemic control. To combat the future variants of SARS-CoV-2, the world needs novel antiviral drugs that are effective at curb viral spreading without introducing additional selective pressure towards resistant variants.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Drug Design/methods , Receptors, Virus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/transmission , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , Humans , Immune Evasion , Mutation , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
12.
J Nat Prod ; 85(1): 284-291, 2022 01 28.
Article in English | MEDLINE | ID: covidwho-1596477

ABSTRACT

We have previously reported that neoechinulin B (1a), a prenylated indole diketopiperazine alkaloid, shows antiviral activities against hepatitis C virus (HCV) via the inactivation of the liver X receptors (LXRs) and the resultant disruption of double-membrane vesicles. In this study, a two-step synthesis of the diketopiperazine scaffold of 1a was achieved by the base-induced coupling of 1,4-diacetyl-3-{[(tert-butyldimethylsilyl)oxy]methyl}piperazine-2,5-dione with aldehydes, followed by the treatment of the resultant coupling products with tetra-n-butylammonium fluoride. Compound 1a and its 16 derivatives 1b-q were prepared using this method. Furthermore, variecolorin H, a related alkaloid, was obtained by the acid treatment of 1a in MeOH. The antiviral evaluation of 1a and its derivatives revealed that 1a, 1c, 1d, 1h, 1j, 1l, and 1o exhibited both anti-HCV and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities. The results of this study indicate that the exomethylene moiety on the diketopiperazine ring is important for the antiviral activities. The antiviral compounds can inhibit the production of HCV and SARS-CoV-2 by inactivating LXRs.


Subject(s)
Alkaloids/pharmacology , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Piperazines/pharmacology , SARS-CoV-2/drug effects , Alkaloids/chemical synthesis , Alkaloids/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line, Tumor , Diketopiperazines/chemistry , Diketopiperazines/pharmacology , Humans , Liver X Receptors/antagonists & inhibitors , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Structure-Activity Relationship , Transcription, Genetic/drug effects
13.
Bioorg Med Chem Lett ; 58: 128526, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1592308

ABSTRACT

The COVID-19 pandemic has drastically impacted global economies and public health. Although vaccine development has been successful, it was not sufficient against more infectious mutant strains including the Delta variant indicating a need for alternative treatment strategies such as small molecular compound development. In this work, a series of SARS-CoV-2 main protease (Mpro) inhibitors were designed and tested based on the active compound from high-throughput diverse compound library screens. The most efficacious compound (16b-3) displayed potent SARS-CoV-2 Mpro inhibition with an IC50 value of 116 nM and selectivity against SARS-CoV-2 Mpro when compared to PLpro and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Discovery , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Thiazoles/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , Coronavirus 3C Proteases/metabolism , Humans , Microbial Sensitivity Tests , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Thiazoles/chemical synthesis , Thiazoles/chemistry
14.
Viruses ; 14(1)2021 12 24.
Article in English | MEDLINE | ID: covidwho-1580407

ABSTRACT

Only a mere fraction of the huge variety of human pathogenic viruses can be targeted by the currently available spectrum of antiviral drugs. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the urgent need for molecules that can be deployed quickly to treat novel, developing or re-emerging viral infections. Sulfated polysaccharides are found on the surfaces of both the susceptible host cells and the majority of human viruses, and thus can play an important role during viral infection. Such polysaccharides widely occurring in natural sources, specifically those converted into sulfated varieties, have already proved to possess a high level and sometimes also broad-spectrum antiviral activity. This antiviral potency can be determined through multifold molecular pathways, which in many cases have low profiles of cytotoxicity. Consequently, several new polysaccharide-derived drugs are currently being investigated in clinical settings. We reviewed the present status of research on sulfated polysaccharide-based antiviral agents, their structural characteristics, structure-activity relationships, and the potential of clinical application. Furthermore, the molecular mechanisms of sulfated polysaccharides involved in viral infection or in antiviral activity, respectively, are discussed, together with a focus on the emerging methodology contributing to polysaccharide-based drug development.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , COVID-19/epidemiology , Polysaccharides/pharmacology , Viruses/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , COVID-19/drug therapy , Heparin/chemical synthesis , Heparin/chemistry , Heparin/pharmacology , Humans , Polysaccharides/chemistry , SARS-CoV-2/drug effects , Structure-Activity Relationship , Sulfates/chemistry , Sulfates/pharmacology , Virus Diseases/drug therapy , Virus Internalization/drug effects , Viruses/pathogenicity
15.
J Med Chem ; 64(24): 18010-18024, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1555591

ABSTRACT

Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.


Subject(s)
Antiviral Agents/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Imino Sugars/pharmacology , Inositol/analogs & derivatives , alpha-Glucosidases/metabolism , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Binding Sites , Chlorocebus aethiops , Crystallography, X-Ray , Dengue Virus/drug effects , Endoplasmic Reticulum/enzymology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/metabolism , Humans , Imino Sugars/chemical synthesis , Imino Sugars/metabolism , Inositol/chemical synthesis , Inositol/metabolism , Inositol/pharmacology , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/drug effects , Vero Cells , alpha-Glucosidases/chemistry
16.
J Med Chem ; 64(24): 17846-17865, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1555306

ABSTRACT

The COVID-19 pandemic is having a major impact on public health worldwide, and there is an urgent need for the creation of an armamentarium of effective therapeutics, including vaccines, biologics, and small-molecule therapeutics, to combat SARS-CoV-2 and emerging variants. Inspection of the virus life cycle reveals multiple viral- and host-based choke points that can be exploited to combat the virus. SARS-CoV-2 3C-like protease (3CLpro), an enzyme essential for viral replication, is an attractive target for therapeutic intervention, and the design of inhibitors of the protease may lead to the emergence of effective SARS-CoV-2-specific antivirals. We describe herein the results of our studies related to the application of X-ray crystallography, the Thorpe-Ingold effect, deuteration, and stereochemistry in the design of highly potent and nontoxic inhibitors of SARS-CoV-2 3CLpro.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/metabolism , Drug Design , HEK293 Cells , Humans , Hydrogen Bonding , Microbial Sensitivity Tests , Molecular Structure , Protein Binding , SARS-CoV-2/enzymology , Stereoisomerism , Vero Cells
17.
Angew Chem Int Ed Engl ; 61(11): e202114619, 2022 03 07.
Article in English | MEDLINE | ID: covidwho-1544209

ABSTRACT

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine Monophosphate/chemical synthesis , Adenosine Monophosphate/chemistry , Alanine/chemical synthesis , Alanine/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Catalysis , Chemistry Techniques, Synthetic/economics , Chemistry Techniques, Synthetic/methods , Cyclization , Glycosylation , Humans , Models, Molecular , Nucleosides/chemistry , Stereoisomerism , Time Factors
18.
Bioorg Med Chem ; 53: 116523, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1525708

ABSTRACT

Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir's limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 µM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Chlorocebus aethiops , Drug Repositioning , Female , Hydroxychloroquine/chemical synthesis , Hydroxychloroquine/toxicity , Male , Mice , Microbial Sensitivity Tests , Stereoisomerism , Vero Cells
19.
ChemMedChem ; 16(22): 3418-3427, 2021 11 19.
Article in English | MEDLINE | ID: covidwho-1525425

ABSTRACT

Currently, limited therapeutic options are available for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We have developed a set of pyrazine-based small molecules. A series of pyrazine conjugates was synthesized by microwave-assisted click chemistry and benzotriazole chemistry. All the synthesized conjugates were screened against the SAR-CoV-2 virus and their cytotoxicity was determined. Computational studies were carried out to validate the biological data. Some of the pyrazine-triazole conjugates (5 d-g) and (S)-N-(1-(benzo[d]thiazol-2-yl)-2-phenylethyl)pyrazine-2-carboxamide 12 i show significant potency against SARS-CoV-2 among the synthesized conjugates. The selectivity index (SI) of potent conjugates indicates significant efficacy compared to the reference drug (Favipiravir).


Subject(s)
Antiviral Agents/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/drug effects , Amides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/toxicity , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/metabolism , Pyrazines/toxicity , Quantitative Structure-Activity Relationship , Vero Cells
20.
Molecules ; 26(22)2021 Nov 21.
Article in English | MEDLINE | ID: covidwho-1524088

ABSTRACT

Plants consistently synthesize and accumulate medically valuable secondary metabolites which can be isolated and clinically tested under in vitro conditions. An advancement with such important phytochemical production has been recognized and utilized as herbal drugs. Bioactive andrographolide (AGL; C20H30O5) isolated from Andrographis paniculate (AP) (Kalmegh) is a diterpenoid lactones having multifunctional medicinal properties including anti-manic, anti-inflammatory, liver, and lung protective. AGL is known for its immunostimulant activity against a variety of microbial infections thereby, regulating classical and alternative macrophage activation, Ag-specific antibody production during immune disorder therapy. In vitro studies with AGL found it to be effective against multiple tumors, neuronal disorders, diabetes, pneumonia, fibrosis, and other diverse therapeutic misadventures. Generally, virus-based diseases like ZIKA, influenza A virus subtype (H1NI), Ebola (EBOV), Dengue (DENV), and coronavirus (COVID-19) epidemics have greatly increased scientific interest and demands to develop more effective and economical immunomodulating drugs with minimal side effects. Trials and in vitro pharmacological studies with AGL and medicinally beneficial herbs might contribute to benefit the human population without using chemical-based synthetic drugs. In this review, we have discussed the possible role of AGL as a promising herbal-chemo remedy during human diseases, viral infections and as an immunity booster.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , Plants, Medicinal/chemistry , Plants, Medicinal/immunology , Virus Diseases/drug therapy , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Diterpenes/chemical synthesis , Diterpenes/therapeutic use , Health , Humans , Immune System/drug effects
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