Synthesis and evaluation of bifunctional anti-HIV agents based on specificCXCR4 antagonists-AZT conjugation

We have previously found that T140, a 14-amino acid residue peptide, inhibi ts infection of target cells by T cell-line-tropic strains of HIV-1 (X4-HIV -1) through its specific binding to a chemokine receptor, CXCR4. Here, we r eport synthesis and evaluation of bifunctional anti-HIV compounds, which ar e composed of T140 analogues and a reverse transcriptase inhibitor, 3 ' -az ido-3 ' -deoxythymidine (AZT). Novel conjugated analogues have been proved to have the ability for controlled release of AZT in neutral aqueous media as well as mouse and feline sera, and high selectivity indexes (SIs, 50% cy totoxic concentration/50% effective concentration) caused by a synergistic effect of two different regenerating agents. Thus, these bifunctional compo unds have several potential advantages. T140 analogues can possibly work as a carrier of AZT targeting T cells due to their specific affinity for CXCR 4 on T cells, A synergistic effect by two types of regenerating agents may enable drug dosage to be reduced, and thus it may effectively suppress toxi c side effects and the appearance of drug-resistant virus. (C) 2001 Elsevie r Science Ltd. All rights reserved.