Pharmacophore identification of a chemokine receptor (CXCR4) antagonist, T22 ([Tyr 5,12 , Lys 7 ]-polyphemusin II), which specifically blocks T cell-line-tropic HIV-1 infection

Tamamura, Hirokazu; Imai, Makoto; Ishihara, Tsunehito; Masuda, Masao; Funakoshi, Hanae; Oyake, Hiromi; Murakami, Tsutomu; Arakaki, Rieko; Nakashima, Hideki; Otaka, Akira; Ibuka, Toshiro; Waki, Michinori; Matsumoto, Aki; Yamamoto, Naoki; Fujii, Nobutaka

doi:10.1016/s0968-0896(98)00061-3

Cited by 63 publications

(49 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considering that chalcone 4 exhibits potent anti-inflammatory activity upon binding to CXCL12 and not to CXCR4, its mechanism of action markedly differs from that of other pharmacological agents acting upon binding to the receptor CXCR4, such as AMD3100 (52), ALX40-4C, or T22/T140 (5,53,54). Analysis of functional properties of these compounds on constitutively active mutants of CXCR4 receptors (55) reveals that, at high doses, AMD3100 and ALX40-4C are weak partial agonists and that T22/T140 is an inverse agonist of the receptor functions.…”

Section: Discussionmentioning

confidence: 99%

Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12

Hachet‐Haas¹,

Balabanian

Rohmer³

et al. 2008

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential.Chemokines are small (8 -10-kDa) secreted proteins that play roles in the normal physiology of the immune system as well as in orchestrating leukocyte recruitment and activation in the context of inflammatory and infectious diseases (1). Most of them belong to one of two major subfamilies: the ␤ or CC chemokines in which two conserved cysteines from the amino terminus are adjacent to each other and the ␣ or CXC chemokines in which these two cysteines are separated by one residue. Chemokine receptors are members of the superfamily of G proteincoupled receptors characterized by seven transmembranespanning regions and coupling to heterotrimeric G proteins.The CXC chemokine stromal cell-derived factor-1 (SDF1), 5 now named CXCL12, binds to and activates the chemokine receptor CXCR4 as well as the more recently identified CXCR7 receptor (19). CXCL12 stimulates a rapid receptor-mediated intracellular calcium mobilization and signaling through a Pertussis toxin-sensitive G i protein. The response to CXCL12 and expression of the CXCR4 receptor occur at a very early stage of embryonic development and appear to be widely used whenever cell migration is required (2). Indeed mice lacking either CXCL12 or CXCR4 die prenatally and exhibit defects in vascular development, neuronal development, hematopoiesis, and cardiogenesis (3-6).Besides the regulation of homeostatic processes, the CXCR4 receptor is implicated in tumor metastasis (7) as well as in infectious and inflammatory diseases....

show abstract

Section: Discussionmentioning

confidence: 99%

Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12

Hachet‐Haas¹,

Balabanian

Rohmer³

et al. 2008

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

show abstract

“…The NMR structure derived for the more active peptide complex had a conformation resembling that of the disulfide parent while the complex with [Cys 4,10 , D-Phe7]-␣-MSH 4 -13 produced more distortion, due to the geometry of ligation ( Figure 15). Tamamura et al [55][56][57] have shown that three peptides with significantly different cyclic constraints, including a zinc complex, bind to CXCR4 (the GPCR coreceptor that interacts with the complex of gp120 and CD4 and block HIV infectivity). T22, a precursor of T134, has 4 Cys residues making two disulfide bonds and a ␤-hairpin conformation in solution.…”

Section: Figure 12mentioning

confidence: 99%

Peptide interactions with G-protein coupled receptors

Marshall

2001

Biopolymers

View full text Add to dashboard Cite

Peptide recognition by G-protein coupled receptors (GPCRs) is reviewed with an emphasis on the indirect approach used to determine the receptor-bound conformation of peptide ligands. This approach was developed in response to the lack of detailed structural information available for these receptors. Recent advances in the structural determination of rhodopsin (the GPCR of the visual system) by crystallography have provided a scaffold for homology modeling of the inactive state of a wide variety of GPCRs that interact with peptide messages. Additionally, the ability to mutate GPCRs and assay compounds of similar chemical structure to test a common binding site on the receptor provides a firm experimental basis for structure-activity studies. Recognition motifs, common in other well-studied systems such as proteolytic enzymes and major histocompatibility class receptors (MHC) are reviewed briefly to provide a basis of comparison. Finally, the development of true peptidomimetics is contrasted with nonpeptide ligands, discovered through combinatorial chemistry. In many systems, the evidence suggests that the peptide ligands bind at the interface between the transmembrane segments and the extracellular loops, while nonpeptide antagonists bind within the transmembrane segments. Plausible models of GPCRs and the mechanism by which they activate G-proteins on binding peptides are beginning to emerge.

show abstract

“…The first low molecular weight antagonist, AMD3100, is a representative example (40). T22 is a representative polypeptide antagonist of CXCR4, which was synthesized with chemical modification from the horseshoe crab hemocytic polypeptides (41)(42)(43). T134 is a small-sized analog of T22 with reduced positive charges, highly potent activity, and significantly less cytotoxicity (41).…”

Section: Cxcr4mentioning

confidence: 99%

Anti-HIV Drug Development Through Computational Methods

Zhang

Yuan

2014

AAPS J

View full text Add to dashboard Cite

Abstract. Although highly active antiretroviral therapy (HAART) is effective in controlling the progression of AIDS, the emergence of drug-resistant strains increases the difficulty of successful treatment of patients with HIV infection. Increasing numbers of patients are facing the dilemma that comes with the running out of drug combinations for HAART. Computational methods play a key role in anti-HIV drug development. A substantial number of studies have been performed in anti-HIV drug development using various computational methods, such as virtual screening, QSAR, molecular docking, and homology modeling, etc. In this review, we summarize recent advances in the application of computational methods to anti-HIV drug development for five key targets as follows: reverse transcriptase, protease, integrase, CCR5, and CXCR4. We hope that this review will stimulate researchers from multiple disciplines to consider computational methods in the anti-HIV drug development process.

show abstract

Pharmacophore identification of a chemokine receptor (CXCR4) antagonist, T22 ([Tyr 5,12 , Lys 7 ]-polyphemusin II), which specifically blocks T cell-line-tropic HIV-1 infection

Cited by 63 publications

References 22 publications

Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12

Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12

Peptide interactions with G-protein coupled receptors

Anti-HIV Drug Development Through Computational Methods

Contact Info

Product

Resources

About