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

Maeda, Kenji; Nakata, Hirotomo; Koh, Yasuhiro; Miyakawa, Taihei; Ogata, Hiromi; Takaoka, Yousuke; Shibayama, Sotaro; Sagawa, Kenji; Fukushima, Daikichi; Moravek, Joseph; Koyanagi, Yoshio; Mitsuya, Hiroaki

doi:10.1128/jvi.78.16.8654-8662.2004

Cited by 217 publications

(195 citation statements)

References 33 publications

(31 reference statements)

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“…When we exploited site-directed mutagenesis by generating a panel of mutant CCR5-expressing cells, and determined the K D values of each CCR5 inhibitor with each mutant CCR5 species, the K D values compiled corroborated our previous results obtained using the mAb replacement assay (11). We found that the binding affinity of AVC to wild-type CCR5 (CCR5 WT ) was the greatest with a K D value of 2.9 nM as compared with SCH-C and TAK-779 with K D values of 16.0 and 30.2 nM, respectively (Table 1).…”

Section: Discussionsupporting

confidence: 59%

“…AVC, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors including TAK-779 and SCH-C ( Fig. 1), preserves RANTES and macrophage inflammatory protein-1␤ binding to CCR5 ϩ cells and their functions, whereas TAK-779 and SCH-C fully block the CC-chemokines/CCR5 interactions (11). AVC reportedly has an extensive and prolonged CCR5 occupancy as examined in phytohemagglutinin-activated peripheral blood mononuclear cells (t1 ⁄ 2 ϳ 9 h) (12) and in circulating lymphocytes in HIV-1-negative and HIV-1-positive individuals (t1 ⁄ 2 of 69 -152 h depending on different AVC doses) (37).…”

mentioning

confidence: 89%

“…Reagents-A CCR5 inhibitor, AVC, was designed and synthesized as previously published (11). Two other CCR5 inhibitors, TAK-779 and SCH-351125 (SCH-C), were synthesized based on the previously published structures (13,14) (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, this implies that the intervention of HIV-1 infection without interrupting physiological CC-chemokine/ CCR5 interactions should be feasible. Indeed, AVC does not potently block the physiologic CC-chemokine/CCR5 interactions, although it highly efficiently suppresses the infection of HIV-1 with IC 50 values of subnanomolar concentrations (11).…”

mentioning

confidence: 99%

“…Aplaviroc (AVC; AK602/ONO4128/873140; Fig. 1), a novel spirodiketopiperazine derivative, represents a CCR5 inhibitor that specifically binds to human CCR5 with a high affinity, greatly blocks HIV-1-gp120/ CCR5 binding, and exerts potent activity against a wide spectrum of laboratory and primary R5-HIV-1 isolates including multidrug-resistant HIV-1 MDR (IC 50 values of 0.2-0.6 nM) (11). AVC, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors including TAK-779 and SCH-C ( Fig.…”

mentioning

confidence: 99%

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Structural and Molecular Interactions of CCR5 Inhibitors with CCR5

Maeda

Das

Ogata-Aoki

et al. 2006

Journal of Biological Chemistry

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152

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We have characterized the structural and molecular interactions of CC-chemokine receptor 5 (CCR5) with three CCR5 inhibitors active against R5 human immunodeficiency virus type 1 (HIV-1) including the potent in vitro and in vivo CCR5 inhibitor aplaviroc (AVC). The data obtained with saturation binding assays and structural analyses delineated the key interactions responsible for the binding of CCR5 inhibitors with CCR5 and illustrated that their binding site is located in a predominantly lipophilic pocket in the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5. Mutations in the CCR5 binding sites of AVC decreased gp120 binding to CCR5 and the susceptibility to HIV-1 infection, although mutations in TM4 and TM5 that also decreased gp120 binding and HIV-1 infectivity had less effects on the binding of CC-chemokines, suggesting that CCR5 inhibition targeting appropriate regions might render the inhibition highly HIV-1-specific while preserving the CC chemokine-CCR5 interactions. The present data delineating residue by residue interactions of CCR5 with CCR5 inhibitors should not only help design more potent and more HIV-1-specific CCR5 inhibitors, but also give new insights into the dynamics of CC-chemokine-CCR5 interactions and the mechanisms of CCR5 involvement in the process of cellular entry of HIV-1.Highly active antiretroviral therapy has brought about a major impact on the acquired immunodeficiency syndrome (AIDS) epidemics in industrially advanced nations (1, 2), however, eradication of HIV-1 2 appears to be currently impossible mainly because of the viral reservoirs remaining in blood and infected tissues (3). Successful antiviral drugs, in theory, exert their virus-specific effects by interacting with viral components such as viral genes or their transcripts without disturbing cellular metabolisms or functions (2). However, at present, no antiretroviral drugs or agents have been demonstrated to be completely specific for HIV-1 and devoid of toxicity or side effects in the therapy of AIDS (4). Limitations of antiviral therapy of AIDS are exacerbated by complicated regimens, emergence of drug-resistant HIV-1 variants (1), and a number of inherent adverse effects (5).Thus, identification of new antiretroviral drugs that have unique mechanisms of action and produce no or least minimal side effects remains an important therapeutic objective (2, 4). CCR5 is a member of the G protein-coupled, seven-transmembrane segment receptors, which comprise the largest superfamily of proteins in the body (6). In 1996, it was revealed that CCR5 serves as one of the two essential coreceptors for HIV-1 entry to human CD4 ϩ cells, thereby serving as an attractive target for possible intervention of HIV-1 infection (7-10). Aplaviroc (AVC; AK602/ONO4128/873140; Fig. 1), a novel spirodiketopiperazine derivative, represents a CCR5 inhibitor that specifically binds to human CCR5 with a high affinity, greatly blocks HIV-1-gp120/ CCR5 binding, and exerts potent activity against a wide spectrum of ...

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Section: Discussionsupporting

confidence: 59%

mentioning

confidence: 89%