SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB.

SARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to long-lasting lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses, which can cause systemic complications.

NOD2/RIG-I Activating Adjuvant Enhances the Efficacy of BCG Vaccine Against Tuberculosis in Mice.

Tuberculosis (TB) caused by (MTB) kills about 1.5 million people each year and the widely used Bacille Calmette-Guérin (BCG) vaccine provides a partial protection against TB in children and adults. Because BCG vaccine evades lysosomal fusion in antigen presenting cells (APCs), leading to an inefficient production of peptides and antigen presentation required to activate CD4 T cells, we sought to boost its efficacy using novel agonists of RIG-I and NOD2 as adjuvants.

SB 9200, a novel agonist of innate immunity, shows potent antiviral activity against resistant HCV variants.

SB 9200 is a novel, first-in-class oral modulator of innate immunity that is believed to act via the activation of the RIG-I and NOD2 pathways. SB 9200 has broad-spectrum antiviral activity against RNA viruses including hepatitis C virus (HCV), norovirus, respiratory syncytial virus, and influenza and has demonstrated activity against hepatitis B virus (HBV) in vitro and in vivo. In phase I clinical trials in chronically infected HCV patients, SB 9200 has been shown to reduce HCV RNA by up to 1.

Antiviral Efficacy and Host Immune Response Induction during Sequential Treatment with SB 9200 Followed by Entecavir in Woodchucks.

SB 9200, an orally bioavailable dinucleotide, activates the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) causing the induction of the interferon (IFN) signaling cascade for antiviral defense. The present study evaluated the overall antiviral response in woodchucks upon induction of immune response, first with SB 9200 followed by Entecavir (ETV) versus reduction of viral burden with ETV followed by SB 9200 immunomodulation. Woodchucks chronically infected with woodchuck hepatitis virus (WHV) were treated orally with SB 9200 (30 mg/kg/day) and ETV (0.

Antiviral Efficacy and Host Innate Immunity Associated with SB 9200 Treatment in the Woodchuck Model of Chronic Hepatitis B.

SB 9200, an oral prodrug of the dinucleotide SB 9000, is being developed for the treatment of chronic hepatitis B virus (HBV) infection and represents a novel class of antivirals. SB 9200 is thought to activate the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) resulting in interferon (IFN) mediated antiviral immune responses in virus-infected cells. Additionally, the binding of SB 9200 to these sensor proteins could also sterically block the ability of the viral polymerase to access pre-genomic RNA for nucleic acid synthesis.

Metabolism, pharmacokinetics, tissue distribution, and stability studies of the prodrug analog of an anti-hepatitis B virus dinucleoside phosphorothioate.

The alkoxycarbonyloxy dinucleotide prodrug R(p), S(p)-2 is an orally bioavailable anti-hepatitis B virus agent. The compound is efficiently metabolized to the active dinucleoside phosphorothioate R(p), S(p)-1 by human liver microsomes and S9 fraction without cytochrome P450-mediated oxidation or conjugation. The conversion of R(p), S(p)-2 to R(p), S(p)-1 appears to be mediated by liver esterases, occurs in a stereospecific manner, and is consistent with our earlier reported studies of serum-mediated hydrolytic conversion of R(p), S(p)-2 to R(p), S(p)-1.

Orally bioavailable anti-HBV dinucleotide acyloxyalkyl prodrugs.

The acyloxyalkyl derivatives of a model anti-HBV dinucleotide were synthesized and evaluated as orally bioavailable prodrugs. Our studies have led to the identification of the first orally bioavailable dinucleotide prodrugs for further therapeutic development against the hepatitis B virus (HBV).

Microwave-assisted functionalization of solid supports for rapid loading of nucleosides.

Ultra-fast and efficient functionalization of solid supports such as controlled-pore glass (CPG), amino methyl polystyrene, and Tentagel has been achieved using microwave-assisted procedures. Both amino- and carboxy-terminated supports are easily prepared within minutes, in a reproducible manner, using microwave-assisted methodologies. The resulting functionalized supports are efficiently coupled to nucleosides using dimethylformamide as a solvent in conjunction with a specially designed reactor and workstation called LOTUS.

Anti-HBV nucleotide prodrug analogs: synthesis, bioreversibility, and cytotoxicity studies.

Several pronucleotide analogs of the model anti-HBV dinucleotide 3'-dA-U(2'OMe) have been synthesized and evaluated for stability, bioreversibility and cytotoxicity. These studies have helped identify potential candidates for further evaluation.

Nucleotide analogs as novel anti-hepatitis B virus agents.

During the past decade, nucleotide analogs have emerged as novel antiviral agents against hepatitis B virus. Adefovir dipivoxil, a prototype phosphonate analog, has been approved for chronic hepatitis B virus therapy, and additional phosphonate analogs and di- and tri-nucleotides are under development. Several innovative prodrug derivatizations have also been reported to improve the oral bioavailability of nucleotide analogs, which usually carry a negative charge.