Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

Alan Lau; Karra M Swinbank; Parvin S Ahmed; Debra L Taylor; Stephen P Jackson; Graeme C M Smith; Mark J O'Connor

doi:10.1038/ncb1250

Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

Nat Cell Biol. 2005 May;7(5):493-500. doi: 10.1038/ncb1250. Epub 2005 Apr 17.

Authors

Alan Lau¹, Karra M Swinbank, Parvin S Ahmed, Debra L Taylor, Stephen P Jackson, Graeme C M Smith, Mark J O'Connor

Affiliation

¹ KuDOS Pharmaceuticals Limited, 327 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.

PMID: 15834407
DOI: 10.1038/ncb1250

Abstract

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.

MeSH terms

Animals
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / metabolism
Cell Death / drug effects
Cell Death / physiology
Cells, Cultured
DNA Repair / drug effects
DNA Repair / physiology
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / metabolism
Drug Resistance, Viral / drug effects
Drug Resistance, Viral / physiology
HIV Infections / drug therapy
HIV Infections / virology*
HIV Integrase / drug effects
HIV Integrase / metabolism
HIV Protease Inhibitors / pharmacology
HIV-1 / drug effects
HIV-1 / physiology*
Humans
Mice
Morpholines / pharmacology
Mutation / genetics
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Pyrones / pharmacology
Tumor Suppressor Proteins / antagonists & inhibitors
Tumor Suppressor Proteins / metabolism
Virus Replication / drug effects
Virus Replication / physiology*

Substances

2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
Cell Cycle Proteins
DNA-Binding Proteins
HIV Protease Inhibitors
Morpholines
Pyrones
Tumor Suppressor Proteins
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Atm protein, mouse
Protein Serine-Threonine Kinases
HIV Integrase