EFFICACY OF FUSION PEPTIDE HOMOLOGS IN BLOCKING CELL-LYSIS AND HIV-INDUCED FUSION

Contrary to earlier reports, we have found that tri- and hexapeptides analogous or homologous with segments of the 23-residue N-terminal fus ion sequence (FS) of the viral transmembrane glycoprotein gp41 (residu es 517-539) did not significantly inhibit HIV-1-induced syncytium form ation, using an uninfected cell-infected cell fusion assay, In contras t, we found that the high molecular weight apolipoprotein A-1 and a 23 -residue analog of the FS, with the phenylalanine residues at position s 524 and 527 replaced with alanine residues, were effective inhibitor s, Although the tripeptides were ineffective as inhibitors of syncytiu m formation, we found a number of them inhibited red cell lysis induce d by the synthetic peptide AVGIGALFLGFLGAAGSTMGARS (based on the HIV-1 gp41 FS), This effect was also seen with apolipoprotein A-1. The Ala( 524,527) analog of the fusion sequence could not be tested in this sys tem because it was hemolytic, We concluded that the smaller peptides w ere effective inhibitors of hemolysis because they interfered with por e formation by the fusion sequence peptide, either by disrupting the p ores or by preventing the peptide from adopting the alpha-helical conf ormation found in the pores, On the other hand, membrane fusion, which is a prelude to syncytium formation, has been shown to require the fu sion sequence in the beta-strand conformation, We argue that small pep tides would be unable to block interaction between such strands, altho ugh larger molecules, such as apolipoprotein A-1 and the Ala(524,527) analog, would be able to do so and thus inhibit fusion, It seems, ther efore, that a successful drug directed against the FS-cell membrane in teraction stage of syncytium formation would need to be of relatively high molecular weight and complexity.