Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives

A peptidic CXCR4 antagonist T140 efficiently blocks the entry of T cell line-tropic strains of HIV-1 (X4-HIV-1) into target cells. In this study, a series of T140 derivatives, replacing the basic amino acid residues with Glu (D-Glu) and/or L-citrulline ( Cit), were synthesized in order to reduce non- specific binding and cytotoxicity. Among them, TE14011 ([Cit(6), D-Glu(8)]-T140 with the C-terminal amide) exhibited strong anti-HIV activity and low cytotoxicity. TE14011 was found to be stable in mouse serum, but unstable in rat liver homogenate due to the deletion of the N- terminal Arg(1)-Arg(2)-L-3-(2-naphthyl) alanine (Nal)(3) residues from the parent peptide. N-Terminal acetylation of TE14011 led to the development of a novel lead compound, Ac-TE14011, which possesses a high selectivity index as well as increased stability in serum and liver homogenate.