The CCR5 Receptor-Based Mechanism of Action of 873140, a Potent Allosteric Noncompetitive HIV Entry Inhibitors⃞

  title={The CCR5 Receptor-Based Mechanism of Action of 873140, a Potent Allosteric Noncompetitive HIV Entry Inhibitors⃞},
  author={Christian Watson and Stephen Jenkinson and Wieslaw M. Kazmierski and Terry Kenakin},
  journal={Molecular Pharmacology},
  pages={1268 - 1282}
4-{[4-({(3R)-1-Butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140) is a potent noncompetitive allosteric antagonist of the CCR5 receptor (pKB = 8.6 ± 0.07; 95% CI, 8.5 to 8.8) with concomitantly potent antiviral effects for HIV-1. In this article, the receptor-based mechanism of action of 873140 is compared with four other noncompetitive allosteric antagonists of CCR5. Although (Z)-(4-bromophenyl){1′-[(2,4… 

Molecular Mechanisms of Biased and Probe-Dependent Signaling at CXC-Motif Chemokine Receptor CXCR3 Induced by Negative Allosteric Modulators

The influence of mutations on the ability of negative allosteric modulators to inhibit chemokine-mediated activation was assessed with the bioluminescence resonance energy transfer–based cAMP and β-arrestin recruitment assay and revealed complex molecular mechanisms governing biased and probe-dependent signaling at CXCR3.

Identification and Characterization of INCB 9471 , an Allosteric Noncompetitive Small-Molecule Antagonist of C-C Chemokine Receptor 5 with Potent Inhibitory Activity against Monocyte Migration and HIV-1 Infection

INCB9471 is described, a potent and specific inhibitor of human CCR5 that has been proven to be safe and efficacious in viral load reduction in phase I and II human clinical trails and suggested that INCB9471 and UK427857 may have different binding sites on C CR5.

Identification and Characterization of INCB9471, an Allosteric Noncompetitive Small-Molecule Antagonist of C-C Chemokine Receptor 5 with Potent Inhibitory Activity against Monocyte Migration and HIV-1 Infection

INB9471 was identified using a primary human monocyte-based radioligand competition binding assay and it potently inhibited macrophage inflammatory protein-1β-induced monocyte migration and infection of peripheral blood mononuclear cells by a panel of R5-HIV-1 strains.

Allosteric Modulation of the Cannabinoid CB1 Receptor

The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.

Pharmacological Characterization of Sch527123, a Potent Allosteric CXCR1/CXCR2 Antagonist

The data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.

Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

In this study, overlapping, yet different binding sites for two high-affinity CXCR3 antagonists are shown, which offer new opportunities for the structure-based design of allosteric modulators for CX CR3.

Blockade of X4-Tropic HIV-1 Cellular Entry by GSK812397, a Potent Noncompetitive CXCR4 Receptor Antagonist

It is demonstrated that GSK812397 has antiviral activity against a broad range of X4-utilizing strains of HIV-1 via a noncompetitive antagonism of the CXCR4 receptor and acceptable pharmacokinetic properties and bioavailability across species.

Interaction of small molecule inhibitors of HIV-1 entry with CCR5.

Pharmacological Characterization of [3H]VUF11211, a Novel Radiolabeled Small-Molecule Inverse Agonist for the Chemokine Receptor CXCR3

Findings indicate that this allosteric inverse agonist radioligand for CXCR3 may facilitate the discovery, characterization, and optimization of allosterics modulators for the chemokine receptor CX CR3.

Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

Three series of compounds synthesized from 12 linear and branched polyamines with 2, 3, 4, 6, or 8 amino groups substituted to produce the corresponding guanidines, biguanides, or phenylguanides inhibited infection by X4 strains, but not by R5 strains, at low micromolar concentrations.



Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonis

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic

Spirodiketopiperazine-Based CCR5 Inhibitor Which Preserves CC-Chemokine/CCR5 Interactions and Exerts Potent Activity against R5 Human Immunodeficiency Virus Type 1 In Vitro

A novel spirodiketopiperazine (SDP) derivative, AK602, which specifically blocked the binding of macrophage inflammatory protein 1α (MIP-1α) to CCR5 with a high affinity, 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.

SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo

  • J. StrizkiSerena Xu B. Baroudy
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM.

Allosteric regulation of CCR5 by guanine nucleotides and HIV-1 envelope.

The biochemical consequences of the interaction between CCR5 and G-proteins are reported and it is shown that the MIP-1beta binding site is allosterically regulated by monovalent cations and that binding of this endogenous agonist is highly temperature sensitive and dependent on divalent cations, characteristic of a G-protein-coupled receptor(GPCR).

A Small Molecule Antagonist of Chemokine Receptors CCR1 and CCR3

It appears that the small molecule chemokine receptor antagonist UCB35625 may interact with a region present in both receptors that inhibits the conformational change necessary to initiate intracellular signaling.

Analysis of the Mechanism by Which the Small-Molecule CCR5 Antagonists SCH-351125 and SCH-350581 Inhibit Human Immunodeficiency Virus Type 1 Entry

The mechanism of action of two inhibitors of CCR5 function are identified, SCH-350581 (AD101) and SCH-351125 (SCH-C), which are more potent than SCH-C at inhibiting HIV-1 replication in primary lymphocytes, as well as viral entry and gp120 binding to cell lines.

CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding.

It is proposed that the interaction of CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation by inhibiting an intramolecular interaction between the agonist-bound extracellular domain and the transmembrane domain.

Multiple active states and oligomerization of CCR5 revealed by functional properties of monoclonal antibodies.

The results suggest the existence of multiple active conformations of CCR5 and indicate that C CR5 oligomers are involved in an internalization process that is distinct from that induced by the receptor's agonists.

Interaction of Chemokine Receptor CCR5 with its Ligands: Multiple Domains for HIV-1 gp120 Binding and a Single Domain for Chemokine Binding

The second extracellular loop of CCR5 is an ideal target site for the development of inhibitors of either chemokine or HIV-1 binding to CCR4, suggesting a complicated pattern of HIV- 1 gp120 binding to different regions of C CR5, but a relatively simple pattern for chemokin binding.