2-MERCAPTOBENZENESULPHONAMIDES AS NOVEL INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE AND REPLICATION

An obligatory requirement in the retroviral life cycle is the integrat ion of the viral dsDNA into the host chrome some, a process performed by viral integrase. The retroviral integrase is able to catalyse at le ast three discrete enzymatic steps. Two of these steps, 3' processing and DNA strand transfer, can be measured in an in vitro assay In the p resence of a duplex oligonucleotide corresponding to the viral long te rminal repeat, recombinant integrase and the divalent cations, Mg2+ or Mn2+. This assay provides an efficient means of testing integrase inh ibitors. As part of our continuous effort in developing novel inhibito rs we examined a series of 2-mercaptobenzenesulphonamides (MBSAs) for their inhibitory activity against human immunodeficiency virus type 1 (HIV-1) integrase. From the list of compounds tested in an assay speci fic for HIV-1 integrase, 26 compounds inhibited the 3' processing and strand transfer step with 50% inhibitory concentration (IC50) values b elow 25 mu M. All the thioether derivatives were inactive. These resul ts were further compared with the ability of MBSAs to protect HIV-l-in fected T4 lymphocyte CEM cells. Among 68 compounds tested, 27 exhibite d antiviral activity in cell-based assays with therapeutic indices of 1-16. All the MBSAs with antiviral activity were also effective inhibi tors of recombinant HIV-1 integrase. Several aromatic disulphides were also tested and found to exhibit moderate antiviral and anti-integras e activities. These data demonstrate that MBSAs can be developed as in hibitors of HIV-1 integrase with the potential for antiviral activity.