Flavonoids from the roots and rhizomes of Sophoratonkinensis and their in vitro anti-SARS-CoV-2 activity / 中国天然药物

Acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had caused a global pandemic since 2019, and posed a serious threat to global health security. Traditional Chinese medicine (TCM) has played an indispensable role in the battle against the epidemic. Many components originated from TCMs were found to inhibit the production of SARS-CoV-2 3C-like protease (3CLpro) and papain-like protease (PLpro), which are two promising therapeutic targets to inhibit SARS-CoV-2. This study describes a systematic investigation of the roots and rhizomes of Sophora tonkinensis, which results in the characterization of 12 new flavonoids, including seven prenylated flavanones (1-7), one prenylated flavonol (8), two prenylated chalcones (9-10), one isoflavanone (11), and one isoflavan dimer (12), together with 43 known compounds (13-55). Their structures including the absolute configurations were elucidated by comprehensive analysis of MS, 1D and 2D NMR data, and time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculations. Compounds 12 and 51 exhibited inhibitory effects against SARS-CoV-2 3CLpro with IC50 values of 34.89 and 19.88 μmol·L-1, repectively while compounds 9, 43 and 47 exhibited inhibitory effects against PLpro with IC50 values of 32.67, 79.38, and 16.74 μmol·L-1, respectively.

High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

Rabdomiólisis grave secundaria a deshidratación hipernatrémica / Severe rhabdomyolysis secondary to severe hypernatraemic dehydration

Introducción: La rabdomiólisis es una enfermedad poco frecuente en pediatría. El objetivo es presentar un paciente en el que se desarrolló secundario a una deshidratación hipernatrémica grave tras una diarrea aguda. Caso clínico: Lactante de 11 meses que consultó por fiebre, vómitos, diarrea y anuria. Presentó convulsión tónico-clónica autolimitada. Ingresó en mal estado general, severamente deshidratado, con escasa reactividad. En las pruebas complementarias destacó acidosis metabólica grave, hipernatremia e insuficiencia renal prerrenal. Al tercer día apreció leve hipotonía axial y elevación de creatín fosfokinasa 75.076 UI/l, interpretado como rabdomiólisis. Se inició hiperhidratación y alcalinización sistémica, con buena respuesta clínica y bioquímica, siendo dado de alta sin secuelas motoras. Conclusiones: La hipernatremia grave está descrita como causa rara de rabdomiólisis e insuficiencia renal. En pacientes críticos es importante un alto índice de sospecha de rabdomiólisis y determinación seriada de la creatín fosfokinasa para su detección y tratamiento precoz.

Introduction: Rhabdomyolysis is a rare paediatric condition. The case is presented of a patient in whom this developed secondary to severe hypernatraemic dehydration following acute diarrhoea. Case report: Infant 11 months of age who presented with vomiting, fever, diarrhoea and anuria for 15 hours. Parents reported adequate preparation of artificial formula and oral rehydration solution. He was admitted with malaise, severe dehydration signs and symptoms, cyanosis, and low reactivity. The laboratory tests highlighted severe metabolic acidosis, hypernatraemia and pre-renal kidney failure (Sodium [Na] plasma 181 mEq/L, urine density> 1030). He was managed in Intensive Care Unit with gradual clinical and renal function improvement. On the third day, slight axial hypotonia and elevated cell lysis enzymes (creatine phosphokinase 75,076 IU/L) were observed, interpreted as rhabdomyolysis. He was treated with intravenous rehydration up to 1.5 times the basal requirements, and he showed a good clinical and biochemical response, being discharged 12 days after admission without motor sequelae. Conclusions: Severe hypernatraemia is described as a rare cause of rhabdomyolysis and renal failure. In critically ill patients, it is important to have a high index of suspicion for rhabdomyolysis and performing serial determinations of creatine phosphokinase for early detection and treatment.

A QSAR study on a series of thiourea derivatives acting as anti-hepatitis C virus agents.

A quantitative structure-activity relationship (QSAR) study was performed on a large series of thiourea derivatives reported by Kang et al. [Bioorg Med Chem Lett (2009), 19, 1950-55 & 6063-68], acting as anti-hepatitis C virus (anti-HCV) agents. The activity of the compounds was found to be significantly correlated with their hydrophobic property and three indicator variables I1, I2 and I3, the first two specifying a negative effect of an alkyl and an aromatic group, respectively on their R-moiety and the third one specifying a negative effect of their Ar-moiety having a nitrogen-containing heterocyclic ring. The whole set containing 85 compounds was divided into two subsets: the training set and the test set containing 61 and 24 compounds, respectively. For the training set, the correlation coefficient (r) and the square of cross-validated correlation coefficient (r2cv) were found to be 0.926 and 0.83, respectively. The correlation obtained suggested that anti-HCV activity of the compounds would depend on their hydrophobic property, conformational flexibility and the steric effects of an alkyl or an aromatic group on the R-moiety. This suggested that the molecules might have significant hydrophobic interactions with the receptor which might be aided by their conformational flexibility, but hindered sterically by an alkyl or an aromatic group on their R-moiety. Using the correlation obtained, some new compounds having activity higher (>8.0) than the most active compound in the existing series were predicted.

Cloning and expression of antiviral/ribosome-inactivating protein from Bougainvillea xbuttiana.

A full-length cDNA encoding ribosome-inactivating/antiviral protein (RIP/AVP)from the leaves of Bougainvillea x buttiana was isolated.The cDNA consisted of 1364 nucleotides with an open reading frame (ORF)of 960 nucleotides encoding a 35.49 kDa protein of 319 amino acids.The deduced amino acid sequence has a putative active domain conserved in RIPs/AVPs and shows a varying phylogenetic relationship to the RIPs from other plant species.The deduced protein has been designated BBAP1 (Bougainvillea x buttiana antiviral protein1).The ORF was cloned into an expression vector and expressed in E.coli as a fusion protein of approximately 78 kDa.The cleaved and purified recombinant BBAP1 exhibited ribosome-inhibiting rRNA N-glycosidase activity,and imparted a high level of resistance against the tobacco mosaic virus (TMV).

In vitro antiviral activity of bael (Aegle marmelos Corr) upon human coxsackieviruses B1-B6.

The in-vitro antiviral activity of a series of compounds in samples extracted from various parts of the Indian holy tree, Bael (Aegle marmelos corr.) were evaluated for their efficacy against human coxsackieviruses B1-B6. The inhibitory concentrations (IC50) for leaves (L1 and L2) stem and stem bark (S1, S2, S3 and S4) fruit (F1 and F2micro) root and root bark (R1 and R2) and pure compound, the marmelide were 1000 microg/ml (for L1 and L2), 1000 microg/ml (for S1, S2, S3 and S4), 1000 microg/ml (for F1) and 500 microg/ml (for F2) 250 microg/ml (for R1) and 500 microg/ml (for R2) and 62.5 microg/ml for marmelide respectively by plaque inhibition assay at 96 hrs. On the other hand, the corresponding value for Ribavirin, a standard antiviral drug, was 2000 microg/ml for the same viruses at the same time period. These concentrations did not exhibit any toxicity to Vero cells, the host subtoxic concentrations were 5000 microg/ml for leaf and stem fractions 2000 microg/ml for fruit fractions 500 and 1000 microg/ml for root fractions 250 microg/ml for marmelide and 2000 microg/ml for Ribavirin. The cytotoxic concentrations were 8000 microg/ml for leaf and stem compounds 4000 mg/ml for fruit; 1000 microg/ml and 2000 microg/ml for root 500 microg/ml for marmelide and 4000 microg/ml for ribavirin at 96 hrs. These were also confirmed by trypan blue dye exclusion test and further passaging of cells. Additionally pretreatment of host cells, virus inactivation, yield reduction and effect of time of addition assays against coxsackievirus B3 suggested that marmelide was most effective as a virucidal agent besides interfering at early events of its replicative cycle like adsorption, penetration, at various steps in single cycle growth curve and effect of time of addition.

An investigation of the conformation of peptide-T and its D-Ala analog by NMR and molecular dynamics simulations.

Peptide-T (ASTTTNYT) and its D-Ala analog (D-ASTTTNYT-NH2) have been designed to block the adsorption of HIV to CD4 receptors on T-cell lymphocytes, thus inhibiting viral infectivity. The conformation of these important peptides has been investigated by 2D-NMR and molecular dynamics simulations. The NMR studies in DMSO show that the peptides exist in solution as a mixture of conformations. beta-Turns and non-specific folded conformations are present in a small proportion in the ensemble of conformations, which is largely dominated by more or less extended structures. This result is in line with molecular dynamics simulations where beta-turns were found to occur with a low frequency and with energies 10 to 17 kcal/mole higher than the global minimum structure. Our findings differ from previous reports on the conformation of peptide-T determined by NMR.

Molecular electrostatic potential mapping and structure-activity relationship for 3-methoxy flavones.

Molecular electrostatic potential (MEP) maps of certain 3-methoxy flavone derivatives having different anti-picornavirus activities have been studied. Geometries of the molecules were optimised and charge distributions computed using the AM1 molecular orbital method. Hybridization displacement charges (HDC) were combined with the Löwdin charge distributions to compute the MEP maps. Reliability of the method of computing MEP maps was tested by studying certain other molecules for which ab initio MEP results are available. The anti-picornavirus activities of the flavones have been shown to be related with negative MEP values in two regions, one near the 3-methoxy group and another in a diagonally opposite region near the substituent attached to the C7 atom of the molecules.

Synthesis of 1-substitutes-5(6)-nitrobenzimidazoles as potential antiviral compounds

Se describe la síntesis de derivados nucleosídicos acíclicos 1-sustituidos del 5(6)-bencimidazol y su evaluación farmacológica como compuestos antivirales. Los compuestos fueron sintetizados utilizando 5(6)-nitrobencimidazol como material de partida con los alcoholes sustituidos, clorometilados apropiados, con el fin de obtener análogos de Acyclovir y Ganciclovir, compuestos antivirales conocidos. La actividad antiviral de estos compuestos fue evaluada utilizando cepas de Herpes simplex 1 y Polivirus 1 y bajo las condiciones ensayadas resultaron inactivos

Antiviral activity of naphthoquinones: I. Lapachol derivatives against enteroviruses

Some derivatives obtained by chemical transformation of lapachol (a natural substance extracted from the core of plants belonging to the family Bignoniaceae) vere studied as to their posible antiviral action. Cell cultures were treated with those substances and then inoculated with poliovirus type 1, echovirus 19 and Coxsackievirus B type 4. Only ß-lapachone, succinamidyl-ß-norlapachone and intermediary of Hooker have shown a significant viral inhibition index to echovirus type 19. Those derivatives had in in vitro ion but they did not cause any harm to the viral particles studied (virucidal action)