ATR Kinase: A Novel Cellular Target for Anti-Retroviral Drug Discovery and Therapy

Ref. No. 02-15


Retroviruses cause devastating diseases and severe pathological conditions in humans: human inmmunodeficiency virus (HIV) provokes the development of the acquired immunodeficiency syndrome (AIDS); human T-cell leukemia virus type I (HTLV I) initiates the adult T-cell leukemia-lymphoma, tropical spastic paraparesis and various myelopathies, among others. Additionally, many animal diseases, affecting livestock and agriculture are known to be caused by retroviruses. Anti-retroviral therapy directed to inhibit viral proteins comprises the viral integrase as the primary target. However, the integrase gene is a subject to a high mutation rate, which leads to drug resistance. To overcome the rapid increase of resistance affecting the therapeutic efficacy, new targets and drugs are needed to improve the patient treatment.

Summary of the Invention

Integration of the retroviral DNA into the host genome is an essential step of the retroviral infection and is sensed as DNA damage by the host cell. Researchers from Fox Chase Cancer Center focused on DNA repair proteins such as DNA-PK (DNA-dependent protein kinase) and its role in facilitating stable retroviral DNA integration. DNA-PK belongs to a large family of PI-3K-related protein kinases that also includes ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3 related) kinases. The researchers demonstrated that the ATR kinase is required for stable retroviral DNA integration and can be inhibited under conditions that do not result in significant inhibition of cell viability, thus is an attractive cellular target for anti-retroviral therapy. Methods for identifying agents that modulate this novel cellular target, chemical compounds and pharmaceutical preparations arising from identification of ATR kinase are also suggested. Inhibitors of ATR kinase or its pathway could impede or interrupt retroviral replication, and the probability of resistance developing to such inhibitors would be relatively low compared to inhibitors of viral genes.

Skalka A.M. and Katz R.A. Retroviral DNA integration and the DNA damage response. Cell Death Differ. 2005 Aug; 12 Suppl 1:971-8

Patent Status: US Patent # US 7,736,848 B2 issued June15, 2010

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