IDENTIFICATION OF A PHOSPHODIESTER HEXANUCLEOTIDE THAT INHIBITS HIV-1INFECTION IN-VITRO ON COVALENT LINKAGE OF ITS 5'-END WITH A DIMETHOXYTRITYL RESIDUE

It has been shown in previous reports that a guanine-rich phosphodiest er oligonucleotide bearing a dimethoxytrityl (DmTr) residue on its 5'- terminal, DmTr-TGGGAGGTGGGTCTG (SA-1042), is an inhibitor of HIV-1 inf ection in vitro, SA-1042 interfered with the attachment of gp120 to th e CD4 receptor and the subsequent entry stage of viral infection, We i nvestigated the structure-activity relationship of the DmTr-conjugated oligomer by using 15-mer oligonucleotides with various nucleotide seq uences. Results show that location of guanine nucleosides at the 5'-te rminal and modification of the 5'-terminal with DmTr are essential for anti-HIV-1 activity, First, substitution of the guanine nucleoside cl ose to the 5'-terminal of SA-1042 with another nucleotide prevented an tiviral activity. Second, the existence of at least three consecutive guanine nucleosides adjacent to the 5'-terminal was required for the a ctivity, Finally, modification of the 5'-terminal was essential for th e activity, Based on these findings, the hexanucleotide, DmTr-TGGGAG, was identified as a potent inhibitor of HIV-1 infection, The hexamer w as found to be capable of inhibiting the binding of gp120 to its recep tor CD4 molecule, and it was also capable of inhibiting accessibility of anti-V3 monoclonal antibody to its ligand V3 peptide.