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ATM kinase inhibition may provide new class of HIV inhibitor
  By David Douglas
NEW YORK (Reuters Health) - Inhibition of ataxia-dependent-mutated (ATM) kinase by the agent KU-55933 suppresses replication of wild-type and drug-resistant HIV-1 in vitro, UK researchers report in the May advance online issue of Nature Cell Biology.
"Our work to date has focused on using KU-55933 in proof-of-concept studies in the research setting -- validating ATM as a novel target for treating HIV-1 infections," senior investigator Dr. Mark J. O'Connor told Reuters Health. This, he added, "represents a novel approach to anti-HIV therapy in that we are targeting a host protein and not a viral one."
Dr. O'Connor of KuDOS Pharmaceuticals and colleagues note that the aim is to inhibit non-essential host cell proteins required for viral replication. ATM is such a protein, apparently not needed for host survival. Treating HIV-1 infected cells with the small molecule inhibitor KU-55933 leads to a deficiency in ATM kinase and retrovirus-induced cell death.
As mentioned, the researchers found that KU-55933 represses replication of both wild-type and drug-resistant HIV-1.
However, because of the novelty of this approach, Dr. O'Connor added, "ATM inhibitors will require further significant preclinical testing before we can conduct clinical studies."
Nat Cell Biol 2005.
Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase Alan Lau1, Karra M. Swinbank2, Parvin S. Ahmed2, Debra L. Taylor2, Stephen P. Jackson1, 3, Graeme C. M. Smith1 & Mark J. O'Connor1
1 KuDOS Pharmaceuticals Limited, 327 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
2 MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
3 The Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB3 1QN, UK.
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.
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