T134, a Small-Molecule CXCR4 Inhibitor, Has No Cross-Drug Resistance with AMD3100, a CXCR4 Antagonist with a Different Structure

Abstract

T22, an analog of polyphemusin II (18 amino acid residues), was found to block 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 acid residues) of T22 with reduced positive charges. T134 exhibited highly potent activity and significantly less cytotoxicity in comparison to that of T22. T134 prevents the anti-CXCR4 monoclonal antibody from binding to peripheral blood mononuclear cells but has no effect on the binding of anti-CCR5 monoclonal antibodies. Since T134 inhibits the binding of stromal cell-derived factor-1 (SDF-1) to MT-4 cells, it seems that T134 prevents HIV-1 entry by binding to CXCR4. The bicyclam AMD3100 has also been shown to block HIV-1 entry via CXCR4 but not via CCR5. Both T134 and AMD3100 are CXCR4 antagonists and low-molecular-weight compounds but have different structures. Our results indicate that T134 is active against wild-type T-tropic HIV-1 strains and against AMD3100-resistant strains.

NMR evidence of charge‐dependent interaction between various PND V3 and CCR5 N‐terminal peptides

“…It has been also shown, especially in the case where the HIV‐1 virus uses CXCR4 as coreceptor that the electrostatic interactions between the charged amino acids of CXCR4 and the V3 region of gp120 are of vital importance for viral entry. This type of interactions has been reported to be crucial for the anti‐HIV‐1 activity that is exhibited by molecules as the T22, T140 and their derivatives 41–44. Authors of this paper have characterized the CCR5Nt—V3 peptides interaction with surface plasmon resonance, light scattering and molecular modeling analyses12, 14, 16, 18 and have shown that electrostatic interactions are the main type of interaction occurring between the peptides.…”

Mechanism of HIV antiretroviral drugs progress toward drug resistance

“…The CXCR4 inhibitor, AMD-3100, blocks HIV-1 entry and inhibits binding of SDF1-a to CXCR4 [114]. Other small molecule inhibitors that block T-tropic HIV-1 have been identified, such as ALX40-4C T22, T134, and T140 [115]. The blocking of CCR5 and CXCR4 could result in selective pressures, which lead HIV-1 to switch to use alternative coreceptors that may be highly beneficial to the virus.…”

Chemokinrezeptor-Antagonisten bei atopischen Erkrankungen

“…Die Substanzen T134 und AMD3100 wurden als blockierende Antagonisten für den CXC-Chemokinrezeptor CXCR4 beschrieben. Sie blockieren die Bindung eines gegen den CXCR4 gerichteten monoklonalen Antikörpers und verhindern den CXCR4 vermittelten HIV-Eintritt [34]. In weiteren Studien wurden klein-molekülige Chemokinrezeptor-Antagonisten, die gegen den CC-Chemokinrezeptor CCR1 gerichtet waren, untersucht.…”