ABSTRACT
Aim: The purpose of this study is to design and synthesize a new series of sulfamethazine derivatives as potent neuraminidase inhibitors. Materials & methods: A sulfamethazine lead compound, ZINC670537, was first identified by structure-based virtual screening technique, then some novel inhibitors X1-X10 based on ZINC670537 were designed and synthesized. Results: Compound X3 exerts the most good potency in inhibiting the wild-type H5N1 NA (IC50 = 6.74 µM) and the H274Y mutant NA (IC50 = 21.09 µM). 150-cavity occupation is very important in determining activities of these inhibitors. The sulfamethazine moiety also plays an important role. Conclusion: Compound X3 maybe regard as a good anti-influenza candidate to preform further study.
[Box: see text].
Subject(s)
Antiviral Agents , Drug Design , Enzyme Inhibitors , Influenza A Virus, H5N1 Subtype , Neuraminidase , Sulfamethazine , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Sulfamethazine/pharmacology , Sulfamethazine/chemical synthesis , Sulfamethazine/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Influenza A Virus, H5N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/enzymology , Structure-Activity Relationship , Humans , Molecular Structure , Molecular Docking SimulationABSTRACT
The frequent mutations of influenza A virus (IAV) have led to an urgent need for the development of innovative antiviral drugs. Glycopolymers offer significant advantages in biomedical applications owing to their biocompatibility and structural diversity. However, the primary challenge lies in the design and synthesis of well-defined glycopolymers to precisely control their biological functionalities. In this study, functional glycopolymers with sulfated fucose and 6'-sialyllactose were successfully synthesized through ring-opening metathesis polymerization and a postmodification strategy. The optimized heteropolymer exhibited simultaneous targeting of hemagglutinin and neuraminidase on the surface of IAV, as evidenced by MU-NANA assay and hemagglutination inhibition data. Antiviral experiments demonstrated that the glycopolymer displayed broad and efficient inhibitory activity against wild-type and mutant strains of H1N1 and H3N2 subtypes in vitro, thereby establishing its potential as a dual-targeted inhibitor for combating IAV resistance.
Subject(s)
Antiviral Agents , Fucose , Influenza A Virus, H1N1 Subtype , Lactose , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Lactose/analogs & derivatives , Lactose/chemistry , Lactose/pharmacology , Fucose/chemistry , Fucose/analogs & derivatives , Fucose/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/drug effects , Drug Resistance, Viral/drug effects , Humans , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Influenza A virus/drug effects , Madin Darby Canine Kidney Cells , Animals , Dogs , Polymers/pharmacology , Polymers/chemistryABSTRACT
Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of cancer, obesity, and viral infection. A target of diphyllin and naturally occurring derivatives is the vacuolar ATPase (V-ATPase) complex. Although diphyllin-related natural products are active with in vitro models for viral entry, the potencies and unknown pharmacokinetic properties limit well-designed in vivo evaluations. Previous studies demonstrated that diphyllin derivatives have the utility of blocking the Ebola virus cell entry pathway. However, diphyllin shows limited potency and poor oral bioavailability in mice. An avenue to improve the potency was used in a new library of synthetic derivatives of diphyllin. Diphyllin derivatives exploiting ether linkages at the 4-position with one-to-three carbon spacers to an oxygen or nitrogen atom provided compounds with EC50 values ranging from 7 to 600 nM potency and selectivity up to >500 against Ebola virus in infection assays. These relative potencies are reflected in the Ebola virus infection of primary macrophages, a cell type involved in early pathogenesis. A target engagement study reveals that reducing the ATPV0a2 protein expression enhanced the potency of diphyllin derivatives to block EBOV entry, consistent with effects on the endosomal V-ATPase function. Despite the substantial enhancement of antiviral potencies, limitations were identified, including rapid clearance predicted by in vitro microsome stability assays. However, compounds with similar or improved half-lives relative to diphyllin demonstrated improved pharmacokinetic profiles in vivo. Importantly, these derivatives displayed suitable plasma levels using oral administration, establishing the feasibility of in vivo antiviral testing.
Subject(s)
Antiviral Agents , Vacuolar Proton-Translocating ATPases , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors , Vacuolar Proton-Translocating ATPases/metabolism , Animals , Mice , Structure-Activity Relationship , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/chemical synthesis , Humans , Molecular Structure , Ebolavirus/drug effects , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Dose-Response Relationship, Drug , Lignans/pharmacology , Lignans/chemistry , Naphthalenes/pharmacology , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Naphthalenes/chemical synthesis , Virus Internalization/drug effectsABSTRACT
Hepatitis B virus (HBV) infection, as a serious global public health issue, is closely related to the immune dysfunction. Herein, thirty-seven 1-(indolin-1-yl)-2-(thiazol-4-yl)ethan-1-one derivatives were prepared as potential immunomodulatory anti-HBV agents. Anti-HBV activity evaluation confirmed compound 11a could significantly suppress the HBV DNA replication in both wild and resistant HBV stains, with IC50 values of 0.13 µM and 0.36 µM, respectively. Preliminary action mechanism studies showed that 11a had an inhibitory effect on cellular HBsAg secretion and could effectively activate TLR7, thereby inducing the secretion of TLR7-regulated cytokines IL-12, TNF-α and IFN-α in human PBMC cells. SPR analysis confirmed that 11a could bind to TLR7 protein with an affinity of 7.06 µM. MD simulation predicted that 11a could form tight interactions with residues in the binding pocket of TLR7. Physicochemical parameters perdition and pharmacokinetic analysis indicated that 11a displayed relatively favorable drug-like properties. Considering all the results, compound 11a might be a promising lead for developing novel immunomodulatory anti-HBV agents.
Subject(s)
Antiviral Agents , Hepatitis B virus , Toll-Like Receptor 7 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Hepatitis B virus/drug effects , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 7/agonists , Structure-Activity Relationship , Molecular Structure , Dose-Response Relationship, Drug , Indoles/chemistry , Indoles/pharmacology , Indoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacology , Thiazoles/chemical synthesis , Virus Replication/drug effects , Microbial Sensitivity Tests , Animals , Hep G2 CellsABSTRACT
The family of human-infecting coronaviruses (HCoVs) poses a serious threat to global health and includes several highly pathogenic strains that cause severe respiratory illnesses. It is essential that we develop effective broad-spectrum anti-HCoV agents to prepare for future outbreaks. In this study, we used PROteolysis TArgeting Chimera (PROTAC) technology focused on degradation of the HCoV main protease (Mpro), a conserved enzyme essential for viral replication and pathogenicity. By adapting the Mpro inhibitor GC376, we produced two novel PROTACs, P2 and P3, which showed relatively broad-spectrum activity against the human-infecting CoVs HCoV-229E, HCoV-OC43, and SARS-CoV-2. The concentrations of these PROTACs that reduced virus replication by 50 % ranged from 0.71 to 4.6 µM, and neither showed cytotoxicity at 100 µM. Furthermore, mechanistic binding studies demonstrated that P2 and P3 effectively targeted HCoV-229E, HCoV-OC43, and SARS-CoV-2 by degrading Mpro within cells in vitro. This study highlights the potential of PROTAC technology in the development of broad-spectrum anti-HCoVs agents, presenting a novel approach for dealing with future viral outbreaks, particularly those stemming from CoVs.
Subject(s)
Antiviral Agents , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Proteolysis/drug effects , Coronavirus 229E, Human/drug effects , Coronavirus OC43, Human/drug effects , Virus Replication/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Structure-Activity Relationship , Drug Development , Lactams , Leucine/analogs & derivatives , Sulfonic AcidsABSTRACT
Protein adenosine diphosphate (ADP)-ribosylation is crucial for a proper immune response. Accordingly, viruses have evolved ADP-ribosyl hydrolases to remove these modifications, a prominent example being the SARS-CoV-2 NSP3 macrodomain, "Mac1". Consequently, inhibitors are developed by testing large libraries of small molecule candidates, with considerable success. However, a relatively underexplored angle in design pertains to the synthesis of structural substrate mimics. Here, we present the synthesis and biophysical activity of novel adenosine diphosphate ribose (ADPr) analogues as SARS-CoV-2 NSP3 Mac1 inhibitors.
Subject(s)
Adenosine Diphosphate Ribose , Antiviral Agents , SARS-CoV-2 , SARS-CoV-2/drug effects , Adenosine Diphosphate Ribose/chemistry , Adenosine Diphosphate Ribose/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Humans , Molecular Structure , COVID-19 Drug Treatment , Protein DomainsABSTRACT
The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has triggered a significant impact on global public health security, it is urgent to develop effective antiviral drugs. Previous studies have found that binding to ACE2 is a key step in the invasion of SARS-CoV-2 into host cells, so virus invasion can be inhibited by blocking ACE2, but there are few reports on this kind of specific inhibitor. Our previous study found that Harringtonine (HT) can inhibit the entry of SARS-CoV-2 spike pseudovirus into ACE2h cells, but its relatively high cytotoxicity limits its further development. Amino acid modification of the active components can increase their solubility and reduce their cytotoxicity. Therefore, in this study, seven new derivatives were synthesized by amino acid modification of its core structure Cephalotaxine. The target compounds were evaluated by cell viability assay and the SARS-CoV-2 spike pseudovirus entry assay. Compound CET-1 significantly inhibited the entry of pseudovirus into ACE2h cells and showed less cytotoxicity than HT. Molecular docking results showed that CET-1 could bind TYR83, an important residue of ACE2, just like HT. In conclusion, our study provided a novel compound with more potential activity and lower toxicity than HT on inhibiting the SARS-CoV-2 spike pseudovirus infection, which makes it possible to be a lead compound as an antiviral drug in the future.
Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents , COVID-19 Drug Treatment , Homoharringtonine , Molecular Docking Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , Amino Acids/chemistry , Amino Acids/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Cell Survival/drug effects , COVID-19/virology , Homoharringtonine/pharmacology , Homoharringtonine/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization/drug effects , Harringtonines/chemistry , Harringtonines/pharmacologyABSTRACT
1H-indole-2,3-dione 3-[4-(4-sulfamoylphenyl)thiosemicarbazones] (6a-j) were evaluated against Para-influenza-3, Reovirus-1, Sindbis, Coxsackie B4 and Punto Toro viruses. New 1-methyl-1H-indole-2,3-dione 3-[4-(4-sulfamoylphenyl)thiosemicarbazones] (7a-c) were synthesized to evaluate the contribution of methyl substitution at position 1- of the indole ring to antiviral activity. The test results showed that compounds 5-trifluoromethoxy- substituted 6c (EC50: 2-9 µM) and 5-bromo- substituted 6f (EC50: 2-3 µM) have non-toxic selective antiviral activity while not all standards are active against Reovirus-1. Molecular docking studies of 6c and 6f were carried out to determine the possible binding positions with Reovirus-1. Trifluoromethoxy and bromine substitutions at position 5- of the indole ring provided selective antiviral activity, while methyl substitution at position 1- of the indole ring significantly decreased the activity and increased toxicity against Reovirus-1.
Subject(s)
Antiviral Agents , Thiosemicarbazones , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Thiosemicarbazones/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/chemical synthesis , Molecular Docking Simulation , Animals , Indoles/pharmacology , Indoles/chemistry , Humans , Structure-Activity RelationshipABSTRACT
Papain-like protease (PLpro) is a promising therapeutic target for its pivotal role in the life cycle of SARS-CoV-2. A series of 1,2,4-oxadiazole derivatives was designed and synthesized via a ring formation strategy based on SARS-CoV-2 PLpro-GRL0617 complex structure. Systematic structure-activity relationship studies revealed that introducing oxadiazole and aryl carboxylic acid moieties to GRL0617 enhanced the enzymatic inhibition activity, affinity, and deubiquitination capacity toward PLpro. 1,2,4-Oxadiazole compounds 13f and 26r, which had PLpro inhibition activity (IC50 = 1.8 and 1.0 µM) and antiviral activity against SARS-CoV-2 (EC50 = 5.4 and 4.3 µM), exhibited good metabolic stability (t1/2 > 93.2 min) and higher plasma exposure (AUC0-t = 17,380.08 and 24,289.76 ng·h/mL) in mice. Especially, compound 26r with moderate oral bioavailability of 39.1% and potent antiviral activity is worthy of further studies in vivo. Our findings provide a new insight for the discovery of antiviral agents targeting PLpro.
Subject(s)
Antiviral Agents , Drug Design , Oxadiazoles , SARS-CoV-2 , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Animals , Antiviral Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Structure-Activity Relationship , SARS-CoV-2/drug effects , Mice , Humans , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Carboxylic Acids/chemical synthesis , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , COVID-19 Drug Treatment , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/metabolismABSTRACT
The increasing frequency of filovirus outbreaks in African countries has led to a pressing need for the development of effective antifilovirus agents. In continuation of our previous research on the antifilovirus activity of monoterpenoid derivatives, we synthesized a series of (+)-fenchol and (-)-isopinocampheol derivatives by varying the type of heterocycle and linker length. Derivatives with an N-alkylpiperazine cycle proved to be the most potent antiviral compounds, with half-maximal inhibitory concentration (IC50) 1.4-20 µÐ against Lenti-EboV-GP infection and 11.3-47 µÐ against Lenti-MarV-GP infection. Mechanism-of-action experiments revealed that the compounds may exert their action by binding to surface glycoproteins (GPs). It was demonstrated that the binding of the synthesized compounds to the Marburg virus GP is less efficient as compared to the Ebola virus GP. Furthermore, it was shown that the compounds possess lysosomotropic properties. Thus, the antiviral activity may be due to dual effects. This study offers new antiviral agents that are worthy of further exploration.
Subject(s)
Antiviral Agents , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Humans , Virus Internalization/drug effects , Structure-Activity Relationship , Ebolavirus/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Animals , Microbial Sensitivity Tests , Chlorocebus aethiops , Marburgvirus/drug effectsABSTRACT
A new series of racemic fluorescent octahydrophenazines (rac-PZ1-11) have been designed and synthesized via the efficient nucleophilic aromatic substitution (SNAr) of tetrafluorobenzenedinitriles (1a-c) and racemic cyclohexane-1,2-diamines (rac-2a and b). The bioactivities of these racemic rac-PZs (20 µM) against herpes simplex virus type-1 (HSV-1) were evaluated by the relative cell viability of Vero cells infected with HSV-1. It was found that rac-PZ3 shows much higher anti-HSV-1 activity than others, with EC50 = 9.2 ± 1.4 µM. Further investigation into the anti-HSV activities of rac-PZ3 and its enantiomers RR- and SS-PZ3 indicates that rac-PZ3 can also efficiently inhibit HSV-2 and even ACV-resistant HSV-2 (EC50 = 11.0 ± 2.3 and 14.9 ± 2.8 µM, respectively), SS-PZ3 has better activities against HSV-1, HSV-2 and ACV-resistant HSV-2 (EC50 = 4.1 ± 1.1, 5.8 ± 1.0 and 7.9 ± 1.2 µM, respectively), but RR-PZ3 has almost no antiviral activities. The primary mechanism study indicates that rac-PZ3 efficiently reverses the HSV-1/2-induced cytopathic effect and suppresses the expression of viral mRNA and proteins. In addition, rac-, RR- and SS-PZ3 possess excellent fluorescence properties with almost the same emission wavelength and high fluorescence quantum yields (ΦF = 90.3-92.3 % in cyclohexane solutions and 54.4-57.3 % in solids) and can target endoplasmic reticulum and cell membrane. The efficient anti-HSV bioactivities and excellent fluorescence of PZ3 prove its potential applications in antiviral therapy and biological imaging.
Subject(s)
Antiviral Agents , Herpesvirus 1, Human , Herpesvirus 2, Human , Animals , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Fluorescent Dyes/chemical synthesis , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Microbial Sensitivity Tests , Molecular Structure , Piperazines/pharmacology , Piperazines/chemistry , Piperazines/chemical synthesis , Structure-Activity Relationship , Vero CellsABSTRACT
ß-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.
Subject(s)
Antiviral Agents , Dioxolanes , Stereoisomerism , Dioxolanes/chemistry , Dioxolanes/pharmacology , Dioxolanes/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Uracil/analogs & derivatives , Uracil/chemistry , Uracil/chemical synthesis , Uracil/pharmacology , Molecular Structure , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/chemical synthesisABSTRACT
In this study, a library of phthalimide Schiff base linked to 1,4-disubstituted-1,2,3-triazoles was designed, synthesised, and characterised by different spectral analyses. All analogues have been introduced for in vitro assay of their antiviral activity against COVID-19 virus using Vero cell as incubator with different concentrations. The data revealed most of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with no or weak cytotoxic effect on Vero cells. Furthermore, in vitro assay was done against this enzyme for all analogues and the results showed two of them have IC50 data by 90 µM inhibitory activity. An extensive molecular docking simulation was run to analyse their antiviral mechanism that found the proper non-covalent interaction within the Mpro protease enzyme. Finally, we profiled two reversible inhibitors, COOH and F substituted analogues that might be promising drug candidates for further development have been discovered.
Subject(s)
Antiviral Agents , Molecular Docking Simulation , Phthalimides , SARS-CoV-2 , Triazoles , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Phthalimides/chemistry , Phthalimides/pharmacology , Phthalimides/chemical synthesis , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Vero Cells , Chlorocebus aethiops , SARS-CoV-2/drug effects , Animals , Microbial Sensitivity Tests , Structure-Activity Relationship , Molecular Structure , Humans , Dose-Response Relationship, Drug , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Models, MolecularABSTRACT
The tobacco mosaic virus coat protein (TMV-CP) is indispensable for the virus's replication, movement and transmission, as well as for the host plant's immune system to recognize it. It constitutes the outermost layer of the virus particle, and serves as an essential component of the virus structure. TMV-CP is essential for initiating and extending viral assembly, playing a crucial role in the self-assembly process of Tobacco Mosaic Virus (TMV). This research employed TMV-CP as a primary target for virtual screening, from which a library of 43,417 compounds was sourced and SH-05 was chosen as the lead compound. Consequently, a series of α-amide phosphate derivatives were designed and synthesized, exhibiting remarkable anti-TMV efficacy. The synthesized compounds were found to be beneficial in treating TMV, with compound 3g displaying a slightly better curative effect than Ningnanmycin (NNM) (EC50 = 304.54 µg/mL) at an EC50 of 291.9 µg/mL. Additionally, 3g exhibited comparable inactivation activity (EC50 = 63.2 µg/mL) to NNM (EC50 = 67.5 µg/mL) and similar protective activity (EC50 = 228.9 µg/mL) to NNM (EC50 = 219.7 µg/mL). Microscale thermal analysis revealed that the binding of 3g (Kd = 4.5 ± 1.9 µM) to TMV-CP showed the same level with NNM (Kd = 5.5 ± 2.6 µM). Results from transmission electron microscopy indicated that 3g could disrupt the structure of TMV virus particles. The toxicity prediction indicated that 3g was low toxicity. Molecular docking showed that 3g interacted with TMV-CP through hydrogen bond, attractive charge interaction and π-Cation interaction. This research provided a novel α-amide phosphate structure target TMV-CP, which may help the discovery of new anti-TMV agents in the future.
Subject(s)
Antiviral Agents , Capsid Proteins , Phosphates , Tobacco Mosaic Virus , Tobacco Mosaic Virus/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Phosphates/chemistry , Phosphates/pharmacology , Structure-Activity Relationship , Molecular Structure , Capsid Proteins/antagonists & inhibitors , Capsid Proteins/chemistry , Capsid Proteins/metabolism , Drug Design , Microbial Sensitivity Tests , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Dose-Response Relationship, Drug , Drug Discovery , Molecular Docking SimulationABSTRACT
Algae-based marine carbohydrate drugs are typically decorated with negative ion groups such as carboxylate and sulfate groups. However, the precise synthesis of highly sulfated alginates is challenging, thus impeding their structure-activity relationship studies. Herein we achieve a microwave-assisted synthesis of a range of highly sulfated mannuronate glycans with up to 17 sulfation sites by overcoming the incomplete sulfation due to the electrostatic repulsion of crowded polyanionic groups. Although the partially sulfated tetrasaccharide had the highest affinity for the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, the fully sulfated octasaccharide showed the most potent interference with the binding of the RBD to angiotensin-converting enzyme 2 (ACE2) and Vero E6 cells, indicating that the sulfated oligosaccharides might inhibit the RBD binding to ACE2 in a length-dependent manner.
Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents , Microwaves , Polysaccharides , SARS-CoV-2 , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Chlorocebus aethiops , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Vero Cells , Polysaccharides/chemistry , Polysaccharides/pharmacology , Polysaccharides/chemical synthesis , Humans , Animals , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Hexuronic Acids/chemistry , Hexuronic Acids/pharmacology , Hexuronic Acids/chemical synthesis , Sulfates/chemistry , Sulfates/pharmacology , Sulfates/chemical synthesis , COVID-19 Drug Treatment , Structure-Activity RelationshipABSTRACT
Tobacco mosaic virus (TMV), as one of the most traditional and extensive biological stresses, poses a serious threat to plant growth and development. In this work, a series of 1-phenyl/tertbutyl-5-amino-4-pyrazole oxadiazole and arylhydrazone derivatives was synthesized. Bioassay evaluation demonstrated that the title compounds (P1-P18) without a "thioether bond" lost their anti-TMV activity, while some of the ring-opening arylhydrazone compounds exhibited superior in vivo activity against TMV in tobacco. The EC50 value of title compound T8 for curative activity was 139 µg/mL, similar to that of ningnanmycin (NNM) (EC50 = 152 µg/mL). Safety analysis revealed that compound T8 had no adverse effects on plant growth or seed germination at a concentration of 250 µg/mL. Morphological observation revealed that compound T8 could restore the leaf tissue of a TMV-stressed host and the leaf stomatal aperture to normal. A mechanism study further revealed that compound T8 not only restored the photosynthetic and growth ability of the damaged host to normal levels but also enhanced catalase (CAT) activity and reduced the content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in the damaged host, thereby reducing the oxidation damage to the host. TMV-green fluorescent protein (GFP) experiments further demonstrated that compound T8 not only slowed the transmission speed of TMV in the host but also inhibited its reproduction. All of the experimental results demonstrated that compound T8 could reduce the oxidative damage caused by TMV stress and regulate the photosynthetic ability of the host, achieving the ability to repair damage, to make the plant grow normally.
Subject(s)
Antiviral Agents , Hydrazones , Nicotiana , Oxadiazoles , Plant Diseases , Tobacco Mosaic Virus , Tobacco Mosaic Virus/drug effects , Tobacco Mosaic Virus/physiology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Hydrazones/pharmacology , Hydrazones/chemistry , Hydrazones/chemical synthesis , Nicotiana/virology , Nicotiana/drug effects , Plant Diseases/virology , Antiviral Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Drug Design , Structure-Activity Relationship , Plant Leaves/chemistry , Plant Leaves/drug effects , Molecular StructureABSTRACT
We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.
Subject(s)
Antiviral Agents , Molluscum contagiosum virus , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Molluscum contagiosum virus/drug effects , Humans , Virus Replication/drug effects , Molluscum Contagiosum/drug therapy , Oligopeptides/pharmacology , Oligopeptides/chemistry , Animals , Cell LineABSTRACT
We have successfully accomplished a catalytic asymmetric total synthesis of entecavir, a first-line antihepatitis B virus medication. The pivotal aspect of our strategy lies in the utilization of a Pd-catalyzed enyne borylative cyclization reaction, enabling the construction of a highly substituted cyclopentene scaffold with exceptional stereoselectivity. Additionally, we efficiently accessed the crucial 1,3-diol enyne system early in our synthetic route through a diarylprolinol organocatalyzed enantioselective cross-aldol reaction and Re-catalyzed allylic alcohol relocation. By strategically integrating these three catalytic protocols, we established a practical pathway for acquiring valuable densely heteroatom-substituted cyclopentene cores.
Subject(s)
Antiviral Agents , Cyclopentanes , Guanine , Hepatitis B virus , Cyclopentanes/chemistry , Cyclopentanes/chemical synthesis , Catalysis , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Stereoisomerism , Molecular Structure , Guanine/chemistry , Guanine/analogs & derivatives , Hepatitis B virus/drug effects , Cyclization , Palladium/chemistryABSTRACT
Mosquito-borne viruses are a major worldwide health problem associated with high morbidity and mortality rates and significant impacts on national healthcare budgets. The development of antiviral drugs for both the treatment and prophylaxis of these diseases is thus of considerable importance. To address the need for therapeutics with antiviral activity, a library of heparan sulfate mimetic polymers was screened against dengue virus (DENV), Yellow fever virus (YFV), Zika virus (ZIKV), and Ross River virus (RRV). The polymers were prepared by RAFT polymerization of various acidic monomers with a target MW of 20 kDa (average Mn â¼ 27 kDa by GPC). Among the polymers, poly(SS), a homopolymer of sodium styrenesulfonate, was identified as a broad spectrum antiviral with activity against all the tested viruses and particularly potent inhibition of YFV (IC50 = 310 pM). Our results further uncovered that poly(SS) exhibited a robust inhibition of ZIKV infection in both mosquito and human cell lines, which points out the potential functions of poly(SS) in preventing mosquito-borne viruses associated diseases by blocking viral transmission in their mosquito vectors and mitigating viral infection in patients.
Subject(s)
Antiviral Agents , Heparitin Sulfate , Polymers , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Heparitin Sulfate/chemistry , Heparitin Sulfate/pharmacology , Animals , Humans , Polymers/chemistry , Polymers/pharmacology , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Biocompatible Materials/chemical synthesis , Culicidae/drug effects , Culicidae/virology , Microbial Sensitivity Tests , Materials Testing , Particle Size , Cell Line , Molecular Structure , Chlorocebus aethiops , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Zika Virus/drug effectsABSTRACT
Given the crucial role of the main protease (Mpro) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of Mpro. Our systematic approach combined an Mpro active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent Mpro inhibitor 84 with an IC50 value of 3.23 nM and a second-order rate constant of inactivation, kinac/Ki, of 448,000 M-1s-1. The open-chain Mpro inhibitor 58, along with the macrocyclic compounds 83 and 84, a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC50 values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic Mpro inhibitors as anti-SARS-CoV-2 agents.