Novel small synthetic HIV-1 V3 crown variants: CCR5 targeting ligands

The CC chemokine receptor 5 (CCR5) antagonism represents a promising pharmacological strategy for therapeutic intervention as it plays a significant role in reducing the severity and progression of a wide range of pathological conditions. Here we designed and generated peptide ligands targeting the chemokine receptor, CCR5, that were derived from the critical interaction sites of the V3 crown domain of envelope protein glycoprotein gp120 (TRKSIHIGPGRAFYTTGEI) of HIV-1 using computational biology approach and the peptide sequence corresponding to this region was taken as the template peptide, designated as TMP-1. The peptide variants were synthesized by employing Fmoc chemistry using polymer support and were labelled with rhodamine B to study their interaction with the CCR5 receptor expressed on various cells. TMP-1 and TMP-2 were selected as the high-affinity ligands from in vitro receptor-binding assays. Specific receptor-binding experiments in activated peripheral blood mononuclear cells and HOS.CCR5 cells indicated that TMP-1 and TMP-2 had significant CCR5 specificity. Further, the functional analysis of TMP peptides using chemotactic migration assay showed that both peptides did not mediate the migration of responsive cells. Thus, template TMP-1 and TMP-2 represent promising CCR5 targeting peptide candidates.