https://users.cs.duke.edu/~brd/Teaching/Bio/asmb/current/Papers/Lit4Docking/Gold_dock.pdf

Development and validation of a genetic algorithm for flexible docking.

Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral 'signatures', double-stranded (ds) RNA, is a replication product of most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard). Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKalpha, IKKbeta and IKKvarepsilon kinases by means of its C-terminal region, leading to the activation of NF-kappaB and IRF3. Overexpression of Cardif results in interferon-beta and NF-kappaB promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I-dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-beta production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.

Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus

Many aspects of the hepatitis C virus (HCV) life cycle have not been reproduced in cell culture, which has slowed research progress on this important human pathogen. Here, we describe a full-length HCV genome that replicates and produces virus particles that are infectious in cell culture (HCVcc). Replication of HCVcc was robust, producing nearly 10(5) infectious units per milliliter within 48 hours. Virus particles were filterable and neutralized with a monoclonal antibody against the viral glycoprotein E2. Viral entry was dependent on cellular expression of a putative HCV receptor, CD81. HCVcc replication was inhibited by interferon-alpha and by several HCV-specific antiviral compounds, suggesting that this in vitro system will aid in the search for improved antivirals.

/pdf/complete-replication-of-hepatitis-c-virus-in-cell-culture-4qr0ko8zoa.pdf

Complete Replication of Hepatitis C Virus in Cell Culture

Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

Viral hepatitis B

Non‐Nucleoside Inhibitors of the Hepatitis C Virus NS5B Polymerase: Discovery and Preliminary SAR of Benzimidazole Derivatives.

Disclosed herein are compounds which inhibit human immunodeficiency virus (HIV) protease activity and inhibit HIV replication in human cells Thus, the compounds are indicated for the treatment of HIV infections The compounds can be represented by formula (I), wherein X is a terminal group, for example, an aryloxycarbonyl, an alkanoyl or an arylalkyl carbamoyl; A is absent or an amino acid or a derived amino acid; either R1 or R2 is hydrogen while the other is alkyl or R?1 and R2? are joined to form a cyclohexane; Q is hydrogen, hydroxy, halo or lower alkoxy; and Y is a terminal group, for example, an alkylamino, alkoxy or an optionally substituted anilino

Protease inhibiting succinic acid derivatives

p56lck is a member of the src family of tyrosine kinases and plays a critical role in the signal transduction events that lead to T cell activation. Ligands for the p56lck SH2 domain have the potential to disrupt the interaction of p56lck with its substrates and derail the signaling cascade that leads to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEEI, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 1999, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the nonpeptidic, monocharged compound, 9S. This molecule displays good binding affinity for the p56lck SH2 domain (K(d) 1 microM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibitory effects on a very early event in T cell activation, namely calcium mobilization.

Nonpeptidic, monocharged, cell permeable ligands for the p56lck SH2 domain.

Anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors with sub-micromolar potency in the cell-based replicon assay.

The reaction of benzeneselenenyl chloride with twenty-two propargyl alcohols in methylene chloride solution is reported. Products of both Markownikoff and anti-Markownikoff regiochemistry are forme...

Pierre L. Beaulieu

Papers

Non‐Nucleoside Inhibitors of the Hepatitis C Virus NS5B Polymerase: Discovery and Preliminary SAR of Benzimidazole Derivatives.

Protease inhibiting succinic acid derivatives

Nonpeptidic, monocharged, cell permeable ligands for the p56lck SH2 domain.

Anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors with sub-micromolar potency in the cell-based replicon assay.

The reaction of some propargyl alcohols with benzeneselenenyl chloride