Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivativesElectronic supplementary information (ESI) available: Fig. S1: behaviors of TE14005 (a), TE14011 and Ac-TE14011 (b) in mouse serum; Fig. S2: behaviors of TE14011 (a), Ac-TE14011 (b), TN14003 (c), Ac-TN14003 (d), TC14012 (e) and Ac-TC14012 (f) in rat liver homogenate; Table S1: characterization data of novel synthetic peptides; HPLC charts for synthetic compounds of TE14005, TE14011 and Ac-TE14011, and for a degraded sample of TE14011 in rat liver homogenate and its co-injection with an authentic compound des-[Arg1, Arg2, Nal3]-TE14011. See http://www.rsc.org/suppdata/ob/b3/b306473p/

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 ([Cit6, D-Glu8]-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 Arg1-Arg2-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-TE 14011, which possesses a high selectivity index as well as increased stability in serum and liver homogenate.