ABSTRACT
The preparation of oseltamivir-bovine serum albumin conjugate (OS-BSA) for use as a multivalent influenza neuraminidase (NA) inhibitor is reported. Briefly, the oseltamivir azidohexyl ester was synthesized and covalently bound via an orthogonal attachment to bicyclononyne-modified BSA using copper-free click chemistry. Primary antiviral assays on NA protein and cellular levels showed that the synthetic multivalent OS-BSA conjugate was a more effective inhibitor than monomeric OS azidohexyl ester. Further investigation of the antiviral mechanism found that the prepared OS-BSA could not only be used as a multivalent NA inhibitor but also acted as an adsorbent for the aggregation of virion particles, contributing to the inhibition of the influenza viral replication cycle. Our findings provide insight into the antiviral mechanism of multivalent NA inhibitors and form a basis for the development of novel antiviral agents.
Subject(s)
Influenza, Human , Oseltamivir , Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Esters/pharmacology , Humans , Neuraminidase/metabolism , Oseltamivir/pharmacology , Serum Albumin, Bovine , Virion/metabolism , Virus ReplicationABSTRACT
The endophytic fungus Diaporthe sp. is known to contain many secondary metabolites, but fatty acid derivatives have rarely been found. In this study, four new fatty acid derivatives (1-4), together with four known compounds (5-8), were isolated from Diaporthe sp., which was obtained from the stem of Ligularia fischeri. The absolute configurations of the new compounds 1-4 were deduced based on spectroscopic technique and J-based coupling constant analysis. Moreover, compound 1 exhibited cytotoxic activities against HCT-8 and MCF-7 cancer cells, and compounds 3 and 4 showed modest selectivity for HCT-8 cells by MTT assay.
Subject(s)
Ascomycota , Ligularia , Ascomycota/chemistry , Cell Line, Tumor , Fatty Acids/pharmacology , Humans , Molecular StructureABSTRACT
We describe the preparation of thiosialoside-modified poly (methyl vinyl ether-alt-maleic anhydride) as second-generation polymeric conjugates for the inhibition of influenza virus infection. These synthetic glycopolymers show significantly enhanced neuraminidase inhibitory and antiviral activity in enzyme and cellular levels, respectively. The polyvalent thiosialosides also exhibit comparable inhibitory activity to the first-line anti-influenza drugs Zanamivir® and Oseltamivir® against the PR8 influenza virus strain in virus growth inhibition assays, which may be attributed to multivalent binding to neuraminidase on the virion particles, leading to the virion aggregation and further inhibiting the attaching/fusion and releasing steps in the influenza virus life-cycle. These findings suggest that attaching monomeric sialoside with neuraminidase inhibitory activity to a polymeric scaffold will synergistically disturb both the early and late stages of influenza virus infection, and provides a basis for the development of efficacious anti-viral agents against both wild-type and drug-resistant mutant strains.
Subject(s)
Antiviral Agents/pharmacology , Influenza A virus/drug effects , Orthomyxoviridae Infections/drug therapy , Polymers/pharmacology , Sialic Acids/pharmacology , Thioglycosides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Madin Darby Canine Kidney Cells/drug effects , Madin Darby Canine Kidney Cells/virology , Microbial Sensitivity Tests , Molecular Structure , Polymers/chemical synthesis , Polymers/chemistry , Sialic Acids/chemical synthesis , Sialic Acids/chemistry , Structure-Activity Relationship , Thioglycosides/chemical synthesis , Thioglycosides/chemistryABSTRACT
An efficient and facile total synthesis of diglycoside Matayoside D isolated from the root bark of Matayba guianensis with antiplasmodial activity have been accomplished in 11 steps with 5% overall yields starting from commercially available glucose and rhamnose. Furthermore, a class of the diglycosidic derivatives with different lengths of the linker and valences were also prepared and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Low valent and short linker attached diglycoside show no enhancement of the antiplasmodial activity while polyvalent conjugates showed enhanced antiplasmodial activity with IC50 value at least 20 fold better than that of the corresponding diglycosidic monomer. The polyvalent diglycoside were non-cytotoxic against normal mammalian cells under 50,000 µg/L.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Glycosides/chemistry , Glycosides/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/toxicity , Click Chemistry , Glycoconjugates/chemical synthesis , Glycoconjugates/chemistry , Glycosides/toxicity , HEK293 Cells , Humans , Structure-Activity RelationshipABSTRACT
Two-armed neutral anion receptors (4,5), were prepared and examined for their anion-binding ability using UV-vis, fluorescence and 1H NMR spectra in DMSO. The results of non-linear curve fitting indicate that 4 or 5 form 1 : 1 stoichiometric complexes with dicarboxylate anions by multiple hydrogen bonding interactions and the sensitivity for recognition of dicarboxylate depends on the chain length of these dicarboxylate anions. Receptors 4 and 5 have no binding ability with acetate, dihydrogen phosphate and the halogen (Cl-, Br-, I-) anions. This demonstrates that receptors 4 or 5 could be used as chemical sensors for some special dicarboxylate anions.