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: 4.44). 09/2004; 78(16):8654-62. DOI: 10.1128/JVI.78.16.8654-8662.2004
Source: PubMed


We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ONO4128/GW873140, which specifically blocked the binding
of macrophage inflammatory protein 1α (MIP-1α) to CCR5 with a high affinity (Kd of ≈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-1MDR) (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-1β 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.

Download full-text


Available from: Yoshio Koyanagi,
30 Reads
  • Source
    • "Maraviroc (MVC) [16,17] is the only CCR5 antagonist that has been licensed for clinical use as an HIV-1 antiretroviral therapy [18]. Other CCR5 antagonist HIV-1 inhibitors that are no longer being pursued for clinical development due to lack of clinical efficacy and/or adverse side effects include vicriviroc (VVC) [19], aplaviroc (APL) [20] and TAK-779 [21]. HIV-1 can develop clinical resistance to CCR5 antagonists by two routes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The CCR5 antagonist maraviroc (MVC) inhibits human immunodeficiency virus type 1 (HIV-1) entry by altering the CCR5 extracellular loops (ECL), such that the gp120 envelope glycoproteins (Env) no longer recognize CCR5. The mechanisms of HIV-1 resistance to MVC, the only CCR5 antagonist licensed for clinical use are poorly understood, with insights into MVC resistance almost exclusively limited to knowledge obtained from in vitro studies or from studies of resistance to other CCR5 antagonists. To more precisely understand mechanisms of resistance to MVC in vivo, we characterized Envs isolated from 2 subjects who experienced virologic failure on MVC. Results Envs were cloned from subjects 17 and 24 before commencement of MVC (17-Sens and 24-Sens) and after virologic failure (17-Res and 24-Res). The Envs cloned during virologic failure showed broad divergence in resistance levels, with 17-Res Env exhibiting a relatively high maximal percent inhibition (MPI) of ~90% in NP2-CD4/CCR5 cells and peripheral blood mononuclear cells (PBMC), and 24-Res Env exhibiting a very low MPI of ~0 to 12% in both cell types, indicating relatively “weak” and “strong” resistance, respectively. Resistance mutations were strain-specific and mapped to the gp120 V3 loop. Affinity profiling by the 293-Affinofile assay and mathematical modeling using VERSA (Viral Entry Receptor Sensitivity Analysis) metrics revealed that 17-Res and 24-Res Envs engaged MVC-bound CCR5 inefficiently or very efficiently, respectively. Despite highly divergent phenotypes, and a lack of common gp120 resistance mutations, both resistant Envs exhibited an almost superimposable pattern of dramatically increased reliance on sulfated tyrosine residues in the CCR5 N-terminus, and on histidine residues in the CCR5 ECLs. This altered mechanism of CCR5 engagement rendered both the resistant Envs susceptible to neutralization by a sulfated peptide fragment of the CCR5 N-terminus. Conclusions Clinical resistance to MVC may involve divergent Env phenotypes and different genetic alterations in gp120, but the molecular mechanism of resistance of the Envs studied here appears to be related. The increased reliance on sulfated CCR5 N-terminus residues suggests a new avenue to block HIV-1 entry by CCR5 N-terminus sulfopeptidomimetic drugs.
    Retrovirology 04/2013; 10(1):43. DOI:10.1186/1742-4690-10-43 · 4.19 Impact Factor
  • Source
    • "Chemokine-induced CCR5 signaling is also blocked by Aplaviroc (Maeda et al., 2004). Co-administration of Aplaviroc with other CCR5 allosteric inhibitors in blocking MIP-1α binding showed an antagonistic effect, indicating that they may share a common site of action on CCR5 (Watson et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pandemic of human immunodeficiency virus type one (HIV-1), the major etiologic agent of acquired immunodeficiency disease (AIDS), has led to over 33 million people living with the virus, among which 18 million are women and children. Until now, there is neither an effective vaccine nor a therapeutic cure despite over 30 years of efforts. Although the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%, an effective vaccine will likely rely on a breakthrough discovery of immunogens to elicit broadly reactive neutralizing antibodies, which may take years to achieve. Therefore, there is an urgency of exploring other prophylactic strategies. Recently, antiretroviral treatment as prevention is an exciting area of progress in HIV-1 research. Although effective, the implementation of such strategy faces great financial, political and social challenges in heavily affected regions such as developing countries where drug resistant viruses have already been found with growing incidence. Activating latently infected cells for therapeutic cure is another area of challenge. Since it is greatly difficult to eradicate HIV-1 after the establishment of viral latency, it is necessary to investigate strategies that may close the door to HIV-1. Here, we review studies on non-vaccine strategies in targeting viral entry, which may have critical implications for HIV-1 prevention.
    Protein & Cell 02/2013; 4(2):86-102. DOI:10.1007/s13238-012-2111-9 · 3.25 Impact Factor
  • Source
    • "Allosteric changes need not be in the same direction (antagonism or potentiation), leading to the possibility that an allosteric modulator could change agonist affinity in one direction and efficacy in another. For example, the CCR5 allosteric modulator aplaviroc minimally affects the binding of the chemokine CCL5 to the receptor but completely blocks CCL5-mediated agonism (Maeda et al., 2004; Watson et al., 2005). Thus, while the high affinity binding of CCL5 is not greatly affected by aplaviroc (suggesting that G-protein binding is not altered by the allosteric effect), the steps leading to G-protein activation and subsequent cellular response are completely blocked. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Seven transmembrane receptors (7TMRs) are nature's prototype allosteric proteins made to bind molecules at one location to subsequently change their shape to affect the binding of another molecule at another location. This paper attempts to describe the divergent 7TMR behaviours (i.e. third party allostery, receptor oligomerization, biased agonism) observed in pharmacology in terms of a homogeneous group of allosteric behaviours. By considering the bodies involved as a vector defined by a modulator, conduit and guest, these activities can all be described by a simple model of functional allostery made up of the Ehlert allosteric model and the Black/Leff operational model. It will be shown how this model yields parameters that can be used to characterize the activity of any ligand or protein producing effect through allosteric interaction with a 7TMR.
    British Journal of Pharmacology 03/2012; 165(6):1659-69. DOI:10.1111/j.1476-5381.2011.01749.x · 4.84 Impact Factor
Show more