NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models.

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility.

Development of a respiratory disease model for enterovirus D68 in 4-week-old mice for evaluation of antiviral therapies.

Enterovirus D68 (EV-D68) is a non-polio enterovirus that affects the respiratory system and can cause serious complications, especially in children and older people with weakened immune systems. As an emerging virus, there are no current antiviral therapies or vaccines available. Our goal was to develop a mouse model of human EV-D68 infection that mimicked the disease observed in humans and could be used for evaluation of experimental therapeutics.

Isolation and identification of compounds from Kalanchoe pinnata having human alphaherpesvirus and vaccinia virus antiviral activity.

Context: Kalanchoe pinnata (Lam.) Pers. (Crassulaceae) is a succulent plant that is known for its traditional antivirus and antibacterial usage.

Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties.

Studies were conducted to determine the performance of four dyes in assessing antiviral activities of compounds against three RNA viruses with differing cytopathogenic properties. Dyes included alamarBlue measured by absorbance (ALB-A) and fluorescence (ALB-F), neutral red (NR), Viral ToxGlo™ (VTG), and WST-1. Viruses were chikungunya, dengue type 2, and Junin, which generally cause 100, 80-90, and 50% maximal cytopathic effect (CPE), respectively, in Vero or Vero 76 cells Compounds evaluated were 6-azauridine, BCX-4430, 3-deazaguanine, EICAR, favipiravir, infergen, mycophenolic acid (MPA), ribavirin, and tiazofurin.

The Iminosugar UV-4 is a Broad Inhibitor of Influenza A and B Viruses ex Vivo and in Mice.

Iminosugars that are competitive inhibitors of endoplasmic reticulum (ER) α-glucosidases have been demonstrated to have antiviral activity against a diverse set of viruses. A novel iminosugar, UV-4B, has recently been shown to provide protection against lethal infections with dengue and influenza A (H1N1) viruses in mice. In the current study, the breadth of activity of UV-4B against influenza was examined ex vivo and in vivo.

Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds.

Compounds were evaluated for antiviral activity in rhabdomyosarcoma (RD) cells against a recent 2014 clinical isolate of enterovirus D68 (EV-D68), a 1962 strain of EV-68D, rhinovirus 87 (RV-87, serologically the same as EV-D68), and enterovirus 71 (EV-71). Test substances included known-active antipicornavirus agents (enviroxime, guanidine HCl, pirodavir, pleconaril, and rupintrivir), nucleobase/nucleoside analogs (3-deazaguanine and ribavirin), and three novel epidithiodiketopiperazines (KCN-2,2'-epi-19, KCN-19, and KCN-21). Of these, rupintrivir was the most potent, with 50% inhibition of viral cytopathic effect (EC50) and 90% inhibition (EC90) of virus yield at 0.

A new oxygen modification cyclooctaoxygen binds to nucleic acids as sodium crown complex.

Background: Oxygen exists in two gaseous and six solid allotropic modifications. An additional allotropic modification of oxygen, the cyclooctaoxygen, was predicted to exist in 1990.

Methods: Cyclooctaoxygen sodium was synthesized in vitro from atmospheric oxygen, or catalase effect-generated oxygen, under catalysis of cytosine nucleosides and either ninhydrin or eukaryotic low-molecular weight RNA.

Influenza Virus H1N1 inhibition by serine protease inhibitor (serpin) antithrombin III.

Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Serpins are also part of the early innate immune response to viral infection that includes mannose binding lectins, soluble CD14, defensins and antimicrobial peptides. Recently, serpin antithrombin III (ATIII) was shown to have broad-spectrum antiviral activity against HIV, HSV and HCV.

Synthesis and biological activity evaluation of 5-pyrazoline substituted 4-thiazolidinones.

A series of novel 5-pyrazoline substituted 4-thiazolidinones have been synthesized. Target compounds were evaluated for their anticancer activity in vitro within DTP NCI protocol. Among the tested compounds, the derivatives 4d and 4f were found to be the most active, which demonstrated certain sensitivity profile toward the leukemia subpanel cell lines with GI₅₀ value ranges of 2.

Antivirally active ribavirin analogues--4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modelling.

Background: Ribavirin is a broad-spectrum antiviral agent that derives some of its activity from inhibition of cellular inosine monophosphate dehydrogenase (IMPDH), resulting in lower guanosine triphosphate (GTP) levels. Here we report the biological activities of three ribavirin analogues.

Methods: Antiviral activities of test compounds were performed by in vitro cytopathic effect inhibition assays against influenza A (H1N1, H3N2 and H5N1), influenza B, measles, parainfluenza type 3 (PIV-3) and respiratory syncytial viruses.

Antiviral agents derived from novel 1-adamantyl singlet nitrenes.

Background: Amantadine constitutes an interesting, diamond crystal lattice-shaped, antivirally active amine with an inhibitory effect on influenza A viruses causing common 'flu' in humans. Unfortunately, amantadine forfeited most of its therapeutic potential because of resistance development in recent influenza A virus isolates. The antiviral efficacy of amantadine congeners can be chemically modified, resulting in re-constitution, improvement and/or extension of antiviral activities mediated by amino-adamantyls.

Synthesis and biological evaluation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines: synthetic methodology, enantioselective total synthesis of epicoccin G, 8,8'-epi-ent-rostratin B, gliotoxin, gliotoxin G, emethallicin E, and haematocin and discovery of new antiviral and antimalarial agents.

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis[bis(trimethylsilyl)amino]trisulfide (23) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (1), 8,8'-epi-ent-rostratin B (2), gliotoxin (3), gliotoxin G (4), emethallicin E (5), and haematocin (6). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.

Vaccine production training to develop the workforce of foreign institutions supported by the BARDA influenza vaccine capacity building program.

In the event of an influenza pandemic, vaccination will be the best method to limit virus spread. However, lack of vaccine biomanufacturing capacity means there will not be enough vaccine for the world's population. The U.

D282, a non-nucleoside inhibitor of influenza virus infection that interferes with de novo pyrimidine biosynthesis.

Background: The discovery of novel influenza virus inhibitors remains an important priority in light of the emergence of drug-resistant viruses. Toward this end, a library of over 6,000 compounds was tested for antiviral activity.

Methods: Strains of influenza virus were evaluated by cytopathic effect (CPE) inhibition and virus yield reduction assays.

In vitro and in vivo efficacy of fluorodeoxycytidine analogs against highly pathogenic avian influenza H5N1, seasonal, and pandemic H1N1 virus infections.

Various fluorodeoxyribonucleosides were evaluated for their antiviral activities against influenza virus infections in vitro and in vivo. Among the most potent inhibitors was 2'-deoxy-2'-fluorocytidine (2'-FdC). It inhibited various strains of low and highly pathogenic avian influenza H5N1 viruses, pandemic H1N1 viruses, an oseltamivir-resistant pandemic H1N1 virus, and seasonal influenza viruses (H3N2, H1N1, influenza B) in MDCK cells, with the 90% inhibitory concentrations ranging from 0.

Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.

The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, which directly combat the infectious agent and recruit additional immune responses. This exuberant cytokine release paradoxically injures the host by triggering leakage from capillaries, tissue edema, organ failure, and shock. Current medical therapies target individual pathogens with antimicrobial agents or directly either blunt or boost the host's immune system.

(-)-Carbodine: enantiomeric synthesis and in vitro antiviral activity against various strains of influenza virus including H5N1 (avian influenza) and novel 2009 H1N1 (swine flu).

Enantiomerically pure cyclopentyl cytosine [(-)-carbodine 1] was synthesized from d-ribose and evaluated for its anti-influenza activity in vitro in comparison to the (+)-carbodine, (+/-)-carbodine and ribavirin. (-)-Carbodine 1 exhibited potent antiviral activity against various strains of influenza A and B viruses.

A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo.

Severe acute respiratory syndrome (SARS) is a highly lethal emerging disease caused by coronavirus SARS-CoV. New lethal animal models for SARS were needed to facilitate antiviral research. We adapted and characterized a new strain of SARS-CoV (strain v2163) that was highly lethal in 5- to 6-week-old BALB/c mice.

Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model.

Phenothiazine and derivatives were tested for inhibition of SARS-CoV replication. Phenothiazine slightly inhibited SARS-CoV replication in a neutral red (NR) uptake assay. Adding a propylamino group to give promazine reduced virus yields (VYR assay) with an EC(90)=8.

Interferon alfacon 1 inhibits SARS-CoV infection in human bronchial epithelial Calu-3 cells.

The primary targets for SARS-CoV infection are the epithelial cells in the respiratory and intestinal tract. The angiotensin-converting enzyme 2 (ACE-2) has been identified as a functional receptor for SARS-CoV. ACE-2 has been shown to be expressed at the apical domain of polarized Calu-3 cells.

Novel 3-sulphonamido-quinazolin-4(3H)-one derivatives: microwave-assisted synthesis and evaluation of antiviral activities against respiratory and biodefense viruses.

We designed and synthesized novel 2,3-disubstituted quinazolin-4(3H)-ones by microwave technique and characterized them by spectral analysis. Synthesized compounds were screened for cytotoxicity and for antiviral activity against influenza A (H1N1, H3N2 and H5N1), severe acute respiratory syndrome corona, dengue, yellow fever, Venezuelan equine encephalitis (VEE), Rift Valley fever, and Tacaribe viruses in cell culture. A neutral red uptake assay was used to determine 50% virus-inhibitory concentrations (EC50) of test compounds and their 50% cytotoxicity concentration (CC50) in uninfected Madin-Darby canine kidney, Vero, and Vero 76 cells; selectivity indices (ratio of CC50 to EC50) were derived from the data.

Effect of oral gavage treatment with ZnAL42 and other metallo-ion formulations on influenza A H5N1 and H1N1 virus infections in mice.

Avian influenza H5N1 infections can cause severe, lethal human infections. Whether influenza A virus treatments effectively ameliorate avian influenza H5N1 human infections is uncertain. The research objective was to evaluate the efficacy of novel zinc and other metallo-ion formulations in two influenza A mouse models.

Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice.

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) was inhibitory to four strains of avian H5N1 influenza virus in MDCK cells, with the 90% effective concentrations ranging from 1.3 to 7.7 microM, as determined by a virus yield reduction assay.

Evaluation of immunomodulators, interferons and known in vitro SARS-coV inhibitors for inhibition of SARS-coV replication in BALB/c mice.

Compounds approved for therapeutic use and in vitro inhibitors of severe acute respiratory syndrome coronavirus (SARS-CoV) were evaluated for inhibition in the mouse SARS-CoV replication model. A hybrid interferon, interferon alpha (IFN-alpha) B/D, and a mismatched double-stranded (ds) RNA interferon (IFN) inducer, Ampligen (poly I:poly C124), were the only compounds that potently inhibited virus titres in the lungs of infected mice as assessed by CPE titration assays. When mice were dosed intraperitoneally (i.