Hybrid Molecules of Small Molecular and Peptidic HIV Fusion Inhibitors.

Since the membrane fusion step is the last chance to block the virus extracellularly, membrane fusion is an important target for anti-human immunodeficiency virus (HIV) agents. Previously, the dimeric derivatives of C34, which are contained in the HIV-1 envelope protein gp41 are found, linked by a disulfide bridge or a pegylated linker at its C-terminus have more potent anti-HIV activity than the C34 peptide monomer, and that bivalent inhibitors crosslinking two peptidomimetic small compounds have more potent anti-HIV activity than the parent small compounds. In the present study, the hybrids of small compounds (7-9) and peptides (SC34 (2) and SC22EK (3)) are designed as heterodimeric molecules (10-15) to compensate for the drawbacks of the above homodimeric molecules. Some hybrid molecules of small compounds (7-9) and peptide SC22EK (3) have remarkably higher anti-HIV activity than peptide SC22EK (3). Crosslinking small compounds and peptides (3) is found to be critical for an increase in anti-HIV activity. Hybrid molecules with small compounds and peptides are useful HIV-1 fusion inhibitors.