SYNTHESIS AND ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ACTIVITIES OF NEW PEPTIDO-NUCLEOSIDE ANALOGS

In order to investigate whether antiproteasic peptides coupled to anti -reverse transcriptase nucleosides can act as inhibitors at the differ ent stages of the HIV life cycle, various peptido-nucleosides were syn thesized using methodologies involving nzotriazol-1-yloxy)-tris(dimeth ylamino)phosphonium hexafluorophosphate (BOP) as a coupling reagent be tween the N-4-cytosinyl moiety and the peptide carboxy terminus. The a nti-HIV-1 activity in MT(4) cells of this new class of compounds and t heir anti-HIV protease activities were determined. Fourteen peptido-nu cleosides have been synthesized and six act against both the HIV-prote ase and viral replication ill vitro. Although the activity of the most potent compounds against HIV was found to be one order of magnitude l ower than that of the parent nucleoside drug 2',3'-dideoxy-3'-thiacyti dine, this new class of compound could be of biological interest. Inde ed, since the in vitro half-lives (t(1/2)) of the hydrolysis of the mo st potent compounds in human plasma were found to be longer than 2.5 h , these analogues could reach the infected cells in their structural i ntegrity. This observation does not exclude that these compounds may e xert their antiviral effects as combined prodrugs through extracellula r or intracellular hydrolysis.