Abstract: This invention provides fragments of HCV NS3 helicase, and crystalline compositions thereof, based on subdomains of HCV helicase protein. The protein fragments are stable, soluble, and structurally sound. They can be expressed at high levels in conventional expressions systems, such as E. coli, to permit efficient, large-scale production for NMR-based screening applications and production of [2H,13C,15N]- and [13C,15N]-labeled polypeptides for structural NMR studies. Helicase fragments of the present invention are useful in the most advanced NMR techniques available, e.g., NMR-based drug discovery techniques such as SAR-by-NMR, in biological assays to discover inhibitors of HCV NS3 helicase, and to evaluate the mechanism of action and substrates for HCV NS3 helicase. Crystals of the present invention are useful for structure-based drug design studies using x-ray crystallographic techniques.

Abstract: Various carbonyl amides are employed in vitro and in vivo as non-nucleoside inhibitors of a reverse transcriptase, and particularly of HIV reverse transcriptase. Therefore, contemplated compounds may be employed in the treatment of HIV infected patients. Further contemplated aspects include pharmaceutical compositions comprising therapeutically effective amounts of contemplated compounds.

Abstract: Various carbonyl amides are employed in vitro and in vivo as non-nucleoside inhibitors of a reverse transcriptase, and particularly of HIV reverse transcriptase. Therefore, contemplated compounds may be employed in the treatment of HIV infected patients. Further contemplated aspects include pharmaceutical compositions comprising therapeutically effective amounts of contemplated compounds.

Abstract: A polymerase inhibitor has first moiety coupled to a second moiety via an optional linker in which the first moiety binds to an initiation nucleotide binding site of a polymerase and forms at least two hydrogen bonds with an RNA template strand that is associated with the polymerase, and in which the second moiety comprised a compound that binds to a site proximal to the nucleotide binding site of the polymerase and thereby increases the affinity of the polymerase inhibitor to the polymerase.

Abstract: This invention provides fragments of HCV NS3 helicase, and crystalline compositions thereof, based on subdomains of HCV helicase protein. The protein fragments are stable, soluble, and structurally sound. They can be expressed at high levels in conventional expressions systems, such as E. coli, to permit efficient, large-scale production for NMR-based screening applications and production of [2H,13C,15N]- and [13C,15N]-labeled polypeptides for structural NMR studies. Helicase fragments of the present invention are useful in the most advanced NMR techniques available, e.g., NMR-based drug discovery techniques such as SAR-by-NMR, in biological assays to discover inhibitors of HCV NS3 helicase, and to evaluate the mechanism of action and substrates for HCV NS3 helicase. Crystals of the present invention are useful for structure-based drug design studies using x-ray crystallographic techniques.

Abstract: Covalent HCV NS4A-NS3 complexes comprising the central hydrophobic domain of native HCV NS4A peptide, a linker, and the HCV NS3 serine protease domain, wherein the hydrophobic domain of native HCV NS4A peptide is tethered by the linker to the amino terminus of the HCV NS3 protease domain.

Abstract: A polymerase inhibitor has first moiety coupled to a second moiety via an optional linker in which the first moiety binds to an initiation nucleotide binding site of a polymerase and forms at least two hydrogen bonds with an RNA template strand that is associated with the polymerase, and in which the second moiety comprised a compound that binds to a site proximal to the nucleotide binding site of the polymerase and thereby increases the affinity of the polymerase inhibitor to the polymerase.

Abstract: The invention relates to the purification and crystallization of hepatitis C virus (HCV) NS3/NS4A polypeptide complex. Also, crystallization conditions for NS3/NS4A are provided. Further, the atomic coordinates for the NS3/NS4A protein are disclosed. Examples of its use for the determination of the three-dimensional atomic structures of HCV NS3/NS4A with substrate(s) or substrate analog(s) or inhibitor complexes are also provided.

Abstract: Covalent HCV NS4A-NS3 complexes comprising the central hydrophobic domain of native HCV NS4A peptide, a linker, and the HCV NS3 serine protease domain, wherein the hydrophobic domain of native HCV NS4A peptide is tethered by the linker to the amino terminus of the HCV NS3 protease domain.