C-terminal octylation rescues an inactive T20 mutant: implications for the mechanism of HIV/SIMIAN immunodeficiency virus-induced membrane fusion.
T20, a synthetic peptide corresponding to a C-terminal segment of the envelope glycoprotein (gp41) of human and simian immunodeficiency viruses, is a potent inhibitor of viral infection. We report here that C-terminal octylation of simian immunodeficiency virus gp41-derived T20 induces a significant increase in its inhibitory potency. Furthermore, when C-terminally octylated, an otherwise inactive mutant in which the C-terminal residues GNWF were replaced by ANAA has potency similar to that of the wild type T20. This effect cannot be explained by a trivial inhibitory effect of the octyl group added to the peptides, because the N-terminally octylated peptides have the same activity as the non-octylated parent peptides. The effects caused by octylation on the oligomerization, secondary structure, and membrane-interaction properties of the peptides were investigated. Our results shed light on the mechanism of inhibition by T20 and provide experimental support for the existence of a pre-hairpin intermediate.
Peisajovich
Sergio G
SG
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Gallo
Stephen A
SA
Blumenthal
Robert
R
Shai
Yechiel
Y
D000595:Amino Acid Sequence; D006367:HeLa Cells; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics* / Q000494:pharmacology; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012191:Retroviridae Proteins / Q000737:chemistry* / Q000235:genetics* / Q000494:pharmacology
D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D012191:Retroviridae Proteins; C082614:SIV envelope protein gp41