T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure

T22, an analog of polyphemusin II (18 amino acid residues), was found to bl ock T-tropic human immunodeficiency virus type 1 (HIV-1) entry into target cells as a CXCR4 inhibitor. We synthesized T134, a small analog (14 amino a cid residues) of T22 with reduced positive charges. T134 exhibited highly p otent activity and significantly less cytotoxicity in comparison to that of T22. T134 prevents the anti-CXCR4 monoclonal antibody from binding to peri pheral blood mononuclear cells but has no effect on the binding of anti-CCR 5 monoclonal antibodies. Since T134 inhibits the binding of stromal cell-de rived factor-1 (SDF-1) to MT-4 cells, it seems that T134 prevents HIV-1 ent ry by binding to CXCR4. The bicyclam AMD3100 has also been shown to block H IV-1 entry via (CXCR4 but not via CCR5. Both T134 and AMD3100 are CXCR4 ant agonists and low-molecular-weight compounds but have different structures. Our results indicate that T134 is active against wild-type T-tropic HIV-1 s trains and against AMD3100-resistant strains.