Exploring the Stereochemistry of CXCR4-Peptide Recognition and Inhibiting HIV-1 Entry with d-Peptides Derived from Chemokines

Abstract

The chemokine receptor CXCR4 is critical for many biological functions, such as B-cell lymphopoiesis, regulation of neuronal cell migration, and vascular development (1-3). In addition, CXCR4 together with another chemokine receptor CCR5 are two principal co-receptors for the cellular entry of the human immunodeficiency virus type 1 (HIV-1) 1 (4 -7). The stromal cell-derived factor-1 (SDF-1␣) is the only known natural ligand of CXCR4 and plays important roles in migration, proliferation, and differentiation of leukocytes (8, 9). The viral macrophage inflammatory protein II (vMIP-II) encoded by human herpesvirus 8 (10) is an antagonistic chemokine ligand of CXCR4 (11, 12). vMIP-II also interacts with other chemokine receptors such as CCR5 and CCR3 and inhibits HIV-1 entry mediated by these co-receptors.CXCR4 and other chemokine receptors belong to the superfamily of seven transmembrane G-protein-coupled receptors (GPCRs) (13). These membrane proteins transmit signals from extracellular ligands to intracellular biological pathways via heterotrimeric G-proteins and have been a major class of therapeutic targets for a wide variety of human diseases (14). As such, characterizing the mechanism of biological recognition between these receptors and their ligands is essential for understanding the physiological or pathological processes that they mediate and devising novel strategies for clinical intervention. For CXCR4, studies have been carried out by a number of laboratories using chimeric chemokine receptors and site-specific mutants to study multiple domains of CXCR4 that are important for interacting with chemokine ligands and HIV-1 (15-23). However, because there is no high resolution crystal structure available for CXCR4 (or any other chemokine receptor) alone or complexed with ligands, the structural and biochemical basis of ligand binding and signaling through these important membrane receptors remains poorly understood.To further define the structure-function relationship of the chemokine receptor-ligand interaction, theoretical computer modeling and site-directed mutagenesis were combined to predict plausible structural models for chemokine receptors and their complexes with ligands, such as interleukin-8 receptor ␤ (24) and CCR5 (25,26). Structural models of CXCR4 and its complex with ligands were also proposed (27, 28). Complementary to modeling and mutational analyses of the receptors,

Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias

“…The ability of DV1 and related peptides to compete for CXCR4 binding has been shown in Sup-T1 cells using the anti-CXCR4 antibody 12G5 (31). We therefore used 12G5 to examine the dose-and time-related effects of 10 nmol/L RCP168 on the surface expression of CXCR4.…”

“…RCP112 is an analogue of viral macrophage inflammatory protein II in which the first 10 amino acids in the NH 2 terminus have been deleted; it has shown a significantly reduced affinity to CXCR4 (30). DVIP is a 21 D-amino acid peptide of NH 2 terminus viral macrophage inflammatory protein II with a higher biological stability (31). Cell migration experiments showed that all three peptides significantly inhibited SDF-1a -induced migration, although RCP168 was the most potent (P = 0.0012), essentially blocking migration completely (Fig.…”

Human immunodeficiency virus gp120-induced apoptosis of human neuroblastoma cells in the absence of CXCR4 internalization

“…Moreover, gp120 and CXCL12 also differ in their regulation of specific cell cycle proteins involved in neuronal survival, namely p53, Rb, and E2F (Khan et al, 2003(Khan et al, , 2005, which are directly and indirectly modulated by AKT. This could depend on differences in the intrinsic efficacies of the two CXCR4 ligands (Khan et al, 2004) and/or the presence of multiple receptor conformations (Baribaud et al, 2001;Zhou et al, 2002). Furthermore, based on recent evidence suggesting that receptor internalization may regulate G protein-coupled receptor (GPCR)-mediated signaling in various ways (Lefkowitz and Shenoy, 2005), we hypothesized that gp120 and CXCL12 may also diverge in their ability to induce CXCR4 internalization.…”

Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

“…Halogenation improves the penetration ability of the aromatic substituent [16]. The extension of peptide sequence with appropriate substitution could induce the resistant mechanism against degradation and enhance the pharmacological properties [57,58].…”