Abstract: The present disclosure is directed to a modified isolated immunoglobulin CH2 domain that specifically binds to an extracellular region of an EphA2 receptor, wherein the amino acid sequence of the modified immunoglobulin CH2 domain includes at least one amino acid substitution, addition or deletion in comparison to a wild type immunoglobulin CH2 domain amino acid sequence, wherein the wild type immunoglobulin CH2 domain amino acid sequence includes SEQ ID NO:1 or SEQ ID NO:2. Heterologous immunoconjugates including fusion proteins and pharmaceutical compositions including the modified isolated immunoglobulin CH2 domain are also disclosed. In addition, methods of treating a disease associated with EphA2 overexpression and methods for killing a target cell expressing EphA2 receptors using the modified isolated immunoglobulin CH2 domain are provided.

Abstract: The present invention relates to the molecular biology and virology of the hepatitis C virus (HCV). An object of the present invention is a method to reproduce in vitro the RNA-dependent RNA polymerase activity of HCV that makes use of sequences contained in the HCV NS5B protein.

Abstract: Diketoacids of Formula (A) are useful as inhibitors of viral polymerases. In particular hepatitis C virus RNA dependent RNA polymerase (HCV RdRp), hepatitis B virus polymerase (HBV pol) and reverse transcriptase of human immunodeficiency virus (HIV RN.) The group R may be broadly chosen and is an organic moiety which contains 2 to 24 carbon atoms and includes an optionally cyclic or heterocyclic group in which the atom directly bonded to the adjacent carbonyl in the diketoacid is part of the ring structure.

Abstract: The present invention relates to the molecular biology and virology of the hepatitis C virus (HCV). An object of the present invention is a method to reproduce in vitro the RNA-dependent RNA polymerase activity of HCV that makes use of sequences contained in the HCV NS5B protein.

Abstract: This is a method for reproducing in vitro the RNA-dependent RNA polymerase activity associated with hepatitis C virus. The method is characterized in that sequences contained in NS5B are used in the reaction mixture. The terminal nucleotidyl transferase activity, a further property of the NS5B protein, can also be reproduced using this method. The method takes advantage of the fact that the NS5B protein, either purified to apparent homogeneity or present in extracts of overproducing organisms, can catalyze the addition of ribonucleotides to the 3′-termini of exogenous or endogenous RNA molecules. The invention also relates to a composition of matter that comprises sequences contained in NS5B, and to the use of these compositions for the set up of an enzymatic test capable of selecting, for therapeutic purposes, compounds that inhibit the enzymatic activity associated with NS5B.

Abstract: The process according to the present invention allows expression and isolation of polypeptides with the proteolytic activity of HCV NS3 protease in a pure, catalytically active form, and in amounts that are sufficient for discovery of NS3 protease inhibitors and for determination of the three-dimensional structure of the NS3 protease. A further subject of the present invention is a procedure that defines the chemical and physical conditions necessary for completion of the proteolytic activity of the above polypeptides. The invention further comprises new compositions of matter (expression vectors) containing nucleotide sequences capable of expressing the above mentioned polypeptides in culture cells. Finally, new compounds of matter are defined, suitable to measure the above proteolytic activity, and useful to develop NS3 protease inhibitors and therefore therapeutic agents for use against HCV. The figure shows the kinetic parameters of HCV NS3 protease using the S3 depsipeptide substrate (SEQ ID NO:45).

Abstract: This is a method for reproducing in vitro the serine protease activity associated with the HCV NS3 protein, that comprises using both of the sequences contained in NS3 and the sequences contained in NS4A. This method takes advantage of the ability of the HCV NS4A protein, or sequences contained therein, to act as a cofactor of the serine protease activity or more generally of the enzymatic activities associated with NS3. Optimal serine protease activity is obtained when NS4A is present in a molar ratio of at least 1:1 with NS3. NS3 and NS4A can also be incorporated in the reaction mixture as NS3-NS4A precursor, as this precursor will generate, by means of an autoproteolytic event, equimolar amounts of NS3 and NS4A. It is also possible to mutate the cleavage site between NS3 and NS4A in a procursor, so that NS4A remains covalently The sequences that do not influence the proteolytic activity of NS3 can subsequently be removed from protease activity.