ku-55933 and HIV-Infections

Chemotherapy that is used to treat human immunodeficiency virus type-1 (HIV-1) infection focuses primarily on targeting virally encoded proteins. However, the combination of a short retroviral life cycle and high mutation rate leads to the selection of drug-resistant HIV-1 variants. One way to address this problem is to inhibit non-essential host cell proteins that are required for viral replication. Here we show that the activity of HIV-1 integrase stimulates an ataxia-telangiectasia-mutated (ATM)-dependent DNA damage response, and that a deficiency of this ATM kinase sensitizes cells to retrovirus-induced cell death. Consistent with these observations, we demonstrate that a novel and specific small molecule inhibitor of ATM kinase activity, KU-55933, is capable of suppressing the replication of both wild-type and drug-resistant HIV-1.

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Death; Cells, Cultured; DNA Repair; DNA-Binding Proteins; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Protease Inhibitors; HIV-1; Humans; Mice; Morpholines; Mutation; Protein Serine-Threonine Kinases; Pyrones; Tumor Suppressor Proteins; Virus Replication

Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Death; Cells, Cultured; DNA Repair; DNA-Binding Proteins; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Morpholines; Protein Serine-Threonine Kinases; Pyrones; Tumor Suppressor Proteins; Virus Replication

Chronicles in Drug Discovery is a series of brief reports on timely topics in the field of drug R&D. This month's chronicles contain the following reports: Targeting DNA repair enzymes instead of viral proteins provides a great advantage in preventing the emergence of resistant mutants. A striking increase in therapeutic approaches for the treatment of IBD has been fueled by an improved understanding of the mechanisms that underlie its pathophysiology. Peptide deformylase inhibitors are under active investigation for bacterial infections and cancer treatment. Dopamine D3 receptors present an attractive target for alcoholism therapy since they are involved in the mechanisms of alcohol dependency and abuse.

Topics: Alcoholism; Amidohydrolases; Animals; Anti-Infective Agents; Antineoplastic Agents; Antiviral Agents; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA-Binding Proteins; Dopamine Antagonists; Enzyme Inhibitors; HIV Infections; HIV-1; Humans; Hydroxamic Acids; Inflammatory Bowel Diseases; Morpholines; Nitriles; Protein Serine-Threonine Kinases; Pyrones; Receptors, Dopamine D3; Tetrahydroisoquinolines; Tumor Suppressor Proteins