tailieunhanh - Báo cáo Y học: Modulation of the oligomeric structures of HIV-1 retroviral enzymes by synthetic peptides and small molecules

The efficacy of antiretroviral agents approved for the treat-ment of HIV-1 infection is limited by the virus’s ability to develop resistance. As such there is an urgent need for new ways of thinking about anti-HIV drug development, and accordingly novel viral and cellular targets critical toHIV-1 replication need to be explored and exploited. The retroviral RNA genome encodes for three enzymes essential for viral replication: HIV-1 protease (PR), HIV-1 reverse transcrip-tase (RT) and HIV-1 integrase (IN). . | Eur. J. Biochem. 269 5103-5111 2002 FEBS 2002 doi REVIEW ARTICLE Modulation of the oligomeric structures of HIV-1 retroviral enzymes by synthetic peptides and small molecules Nicolas Sluis-Cremer1 and Gilda Tachedjian2 1 Department of Medicine Division of Infectious Diseases University of Pittsburgh PA USA 2AIDS Molecular Biology Unit Macfarlane Burnet Institute for Medical Research and Public Health Melbourne Victoria Australia The efficacy of antiretroviral agents approved for the treatment of HIV-1 infection is limited by the virus s ability to develop resistance. As such there is an urgent need for new ways of thinking about anti-HIV drug development and accordingly novel viral and cellular targets critical to HIV-1 replication need to be explored and exploited. The retroviral RNA genome encodes for three enzymes essential for viral replication HIV-1 protease PR HIV-1 reverse transcriptase RT and HIV-1 integrase IN . The enzymatic functioning of each of these enzymes is entirely dependent on their oligomeric structures suggesting that inhibition of subunit-subunit assembly or modulation of their quaternary structures provide alternative targets for HIV-1 inhibition. This review discusses the recent advances in the design and or identification of synthetic peptides and small molecules that specifically target the subunit-subunit interfaces of these retroviral enzymes resulting in the inactivation of their enzymatic functioning. Keywords protease reverse transcriptase integrase oligomeric structure inhibiting protein-protein interactions. In 1983 HIV was identified as the etiologic agent of AIDS 1 2 . During the past 18 years a tremendous effort has been placed in the identification and or development of compounds that effectively attenuate HIV-1 infection. To date 16 anti-HIV agents have been approved by the United States FDA for administration to HIV-1 infected individuals. These antiviral agents target the active sites of two .