Structure–activity relationship study of the plasma membrane translocating potential of a short peptide from HIV-1 Tat protein

Abstract

Tat, a 86-amino acid protein involved in thereplication of Human Immunodeficiency Virus type 1(HIV-1), is able to translocate efficiently throughthe plasma membrane and to reach the nucleus totransactivate the viral genome. The region 37–72 ofthe Tat protein, centered on a cluster of basicamino acids, has been assigned to this translocationactivity. Recent data in our group have attributedthis membrane translocating activity to a peptideextending from residues 48 to 60, which contains acluster of eight basic amino acids within a linearsequence of nine residues. Internalization of thispeptide into cells occurred within minutes atconcentrations as low as 100 nM. In order to definemore precisely the involvement of these basic aminoacids in peptide translocation, several analoguescarrying deletions or substitutions of one, orseveral, of the basic residues were synthesized andtested for their cellular uptake and nucleartranslocation. A direct correlation between theoverall charge of the peptide and its cellinternalization was found. In addition, the covalentlinkage of this short basic peptide allows theefficient translocation of a non-membrane permeant peptide.