Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro.

Department of Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Journal of Virology (Impact Factor: 5.08). 09/2004; 78(16):8654-62. DOI: 10.1128/JVI.78.16.8654-8662.2004
Source: PubMed

ABSTRACT We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ONO4128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1alpha (MIP-1alpha) to CCR5 with a high affinity (K(d) of approximately 3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1(MDR)) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1beta binding to CCR5(+) cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The chemokine receptors CCR5 and CXCR4 are the two major coreceptors for HIV entry. Numerous efforts have been made to develop a new class of anti-HIV agents that target these coreceptors as an additional or alternative therapy to standard HAART. Among the CCR5 inhibitors developed so far, maraviroc is the first drug that has been approved by the US FDA for treating patients with R5 HIV-1. Although many CXCR4 inhibitors, some of which are highly active and orally bioavailable, have also been studied, they are still at preclinical stages or have been suspended during development. Importantly, the interaction between CXCR4 and its ligand SDF-1 is involved in various disease conditions, such as cancer cell metastasis, leukemia cell proliferation, rheumatoid arthritis and pulmonary fibrosis. Therefore, CXCR4 inhibitors have potential as novel therapeutics for the treatment of these diseases as well as HIV infection.
    Future Microbiology 07/2010; 5(7):1025-39. · 4.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Based on the attrition rate of CCR5 small molecule antagonists in the clinic the discovery and development of next generation antagonists with an improved pharmacology and safety profile is necessary. Herein, we describe a combined molecular modeling, CCR5-mediated cell fusion, and receptor site-directed mutagenesis approach to study the molecular interactions of six structurally diverse compounds (aplaviroc, maraviroc, vicriviroc, TAK-779, SCH-C and a benzyloxycarbonyl-aminopiperidin-1-yl-butane derivative) with CCR5, a coreceptor for CCR5-tropic HIV-1 strains. This is the first study using an antifusogenic assay, a model of the interaction of the gp120 envelope protein with CCR5. This assay avoids the use of radioactivity and HIV infection assays, and can be used in a high throughput mode. The assay was validated by comparison with other established CCR5 assays. Given the hydrophobic nature of the binding pocket several binding models are suggested which could prove useful in the rational drug design of new lead compounds.
    Virology 03/2011; · 3.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A conserved amino acid within a protein family testifies to a significance of the residue. In the center of transmembrane helix (TM)-5, position V:13/5.47, an aromatic amino acid is conserved among class A 7TM receptors. However, in 37% of chemokine receptors - a subgroup of 7TM receptors - it is a leucine indicating an altered function. Here we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity. The activity of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40), and [L208F;G286F]-CCR5 (V:13/5.47;VII:09/7.42) were assessed in G protein- and β-arrestin-coupled signaling. Computational modeling inferred changes in amino acid conformation. [L203F]-CCR5 increased the basal level of G protein-coupling (20-70% of Emax ) and β-arrestin recruitment (50% of Emax ) with 3-fold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr-244 in TM-6 (VI:09/6.44) moved toward TM-5 in silico, consistent with its previously shown function for CCR5 activation. On [L208F;G286F]-CCR5 the antagonist aplaviroc was converted to a superagonist. The results imply that an aromatic amino acid in the center of TM-5 controls the level of activity. Furthermore, Ile-116 acts as a gate for the movement of Tyr-244 toward TM-5 in the active state, a mechanism proposed previously for the β2 -adrenoceptor. The results provide an understanding of chemokine receptor function and thereby knowledge for the development of biased and non-biased antagonists and inverse agonists.
    British Journal of Pharmacology 12/2013; · 5.07 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014