Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5

Nishikawa, Masao; Takashima, Katsunori; Nishi, Toshiya; Furuta, Rie; Kanzaki, Naoyuki; Yamamoto, Yoshio; Fujisawa, Jun–ichi

doi:10.1128/aac.49.11.4708-4715.2005

Cited by 59 publications

(44 citation statements)

References 51 publications

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“…For example, TAK-779 is the only CCR5 antagonist used in the first reported CCR5 mutagenesis study (Dragic et al, 2000); in the next similar study, SCH-C and AD101, which belongs to the same structure class, were evaluated (Tsamis et al, 2003). In two other studies, either TAK-220 (Nishikawa et al, 2005) or TAK-779 (Seibert et al, 2006) was investigated along with CCR5 inhibitors from Schering-Plough. Furthermore, none of these studies included the only marketed CCR5 antagonist MVC and the other clinically most advanced CCR5 antagonist VVC.…”

Section: Discussionmentioning

confidence: 99%

“…However, the majority of these studies only focused on one or two classes of small molecule CCR5 inhibitors (Dragic et al, 2000;Tsamis et al, 2003;Nishikawa et al, 2005;Seibert et al, 2006). For example, TAK-779 is the only CCR5 antagonist used in the first reported CCR5 mutagenesis study (Dragic et al, 2000); in the next similar study, SCH-C and AD101, which belongs to the same structure class, were evaluated (Tsamis et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The small-molecule CCR5 antagonists sit in the pocket formed by the transmembrane (TM) domains of CCR5 (Dragic et al, 2000;Tsamis et al, 2003;Nishikawa et al, 2005;Maeda et al, 2006;Seibert et al, 2006), whereas HIV gp120 binds to the outer surface of CCR5, mainly by making contact with the N terminus and the second extracellular loop (ECL) of CCR5 (Rucker et al, 1996;Doranz et al, 1997;Dragic et al, 1998;Farzan et al, 1998;Rabut et al, 1998;Ross et al, 1998;Blanpain et al, 1999;Howard et al, 1999;Dragic, 2001). Alanine scanning mutagenesis studies of CCR5 revealed that several key residues required for the small molecule CCR5 antagonists to block HIV entry are located in the TM domains (Dragic et al, 2000;Tsamis et al, 2003;Nishikawa et al, 2005;Maeda et al, 2006;Seibert et al, 2006). These residues were identified by studying one or two classes of CCR5 antagonists.…”

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confidence: 99%

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Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Kondru

Zhang²,

Ji³

et al. 2007

Mol Pharmacol

174

189

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In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of smallmolecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5 antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5 homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better resistance profile.Human immunodeficiency virus (HIV) enters the host cell via the interaction of the viral envelope protein gp160 and the receptor/coreceptors on host cell surface. The majority of primary HIV-1 strains use CCR5 as coreceptor (termed R5 virus), whereas some viruses are able to use another chemokine receptor, CXCR4, as coreceptor (termed X4 virus) or use both CCR5 and CXCR4 as coreceptors (termed R5X4 virus). Because CCR5 is the predominant coreceptor for clinical HIV isolates, and the normal physiology within the human genetic knockout population, CCR5 has become a very attractive target for anti-HIV therapy. A number of small molecule CCR5 antagonists have been identified that demonstrated potent antiviral effects both in cell culture and in clinical trials.TAK-779, a quaternary ammonium anilide, was the first small molecule CCR5 antagonist reported (Baba et al., 1999). This compound was terminated as a result of poor oral availability. Two structurally diverse followers TAK-220 and TAK-652 are both in clinical trials (Imamura et al., 2006;Seto et al., 2006). Several other small molecule CCR5 antagonists with good potency and/or pharmacological properties have also been reported by other pharmaceutical companies. These include SCH-C (SCH-351125), vicriviroc (VVC, SCH-D, SCH-417690), aplaviroc (APL, AK602, GW873140), and maraviroc (MVC, UK-427,857). SCH-C is an oximino-piperidino-piperidine amide (Palani et al., 2002) that showed potent antiviral activity in vivo. However, its clinical development was terminated as a result of HERG inhibitory activity. SCH-D is the next generation compound of SCH-C, which is in late stage clinical development. SCH-D showed better oral availability, potency, safety, and pharmacological properties than SCH-C Article, publication d...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Kondru

Zhang²,

Ji³

et al. 2007

Mol Pharmacol

174

189

View full text Add to dashboard Cite

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“…Current models of HIV-1 gp120-CCR5 binding propose two critical points of contact: (i) between the gp120 V3 base-bridging sheet and the CCR5 N terminus and (ii) between the V3 tip and the body of CCR5 (12-14, 23, 24, 37, 38). The hydrophobic patch in the V3 tip may interact with the hydrophobic pocket thought to be formed by the membrane-spanning helices of CCR5 (19,40,54,62). Although the stem that separates the V3 base and tip can tolerate both sequence variation and conformational flexibility (38,42), changes in length appear to be more disruptive of chemokine receptor binding.…”

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confidence: 99%

A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer

Xiang

Finzi

Pacheco

et al. 2010

J Virol

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Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 ␤2, ␤19, ␤20, and ␤21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.

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“…The binding of these agents locks the receptor in a conformation the virus is unable to recognize (14,25,32,37,51,54). The CCR5 coreceptor antagonists most advanced in development are maraviroc (MVC) and vicriviroc (VCV).…”

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confidence: 99%

Structure-Function Analysis of Human Immunodeficiency Virus Type 1 gp120 Amino Acid Mutations Associated with Resistance to the CCR5 Coreceptor Antagonist Vicriviroc

Ogert¹,

Ba²,

Yan³

et al. 2009

J Virol

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Vicriviroc (VCV) is a small-molecule CCR5 coreceptor antagonist currently in clinical trials for treatment of R5-tropic human immunodeficiency virus type 1 (HIV-1) infection. With this drug in development, identification of resistance mechanisms to VCV is needed to allow optimal outcomes in clinical practice. In this study we further characterized VCV resistance in a lab-adapted, VCV-resistant RU570 virus (RU570-VCV res ). We show that K305R, R315Q, and K319T amino acid changes in the V3 loop, along with P437S in C4, completely reproduced the resistance phenotype in a chimeric ADA envelope containing the C2-V5 region from RU570 passage control gp120. The K305R amino acid change primarily impacted the degree of resistance, whereas K319T contributed to both resistance and virus infectivity. The P437S mutation in C4 had more influence on the relative degree of virus infectivity, while the R315Q mutation contributed to the virus concentrationdependent phenotypic resistance pattern observed for RU570-VCV res . RU570-VCV res pseudovirus entry with VCV-bound CCR5 was dramatically reduced by Y10A, D11A, Y14A, and Y15A mutations in the N terminus of CCR5, whereas these mutations had less impact on entry in the absence of VCV. Notably, an additional Q315E/I317F substitution in the crown region of the V3 loop enhanced resistance to VCV, resulting in a stronger dependence on the N terminus for viral entry. By fitting the envelope mutations to a molecular model of a recently described docked N-terminal CCR5 peptide consisting of residues 2 to 15 in complex with HIV-1 gp120 CD4, potential new interactions in gp120 with the N terminus of CCR5 were uncovered. The cumulative results of this study suggest that as the RU570 VCV-resistant virus adapted to use the drug-bound receptor, it also developed an increased reliance on the N terminus of CCR5.CCR5 antagonists inhibit human immunodeficiency virus type 1 (HIV-1) entry by binding within a pocket formed by the transmembrane domains of CCR5. The binding of these agents locks the receptor in a conformation the virus is unable to recognize (14,25,32,37,51,54). The CCR5 coreceptor antagonists most advanced in development are maraviroc (MVC) and vicriviroc (VCV). MVC, marketed as Selzentry, is approved for use in treatment-experienced adult patients with R5-tropic HIV-1 infection that is resistant to multiple antiretroviral agents (18), and VCV is currently being evaluated in phase II and phase III clinical trials (19,50). With the ongoing clinical development of HIV-1 coreceptor antagonists, further studies are needed regarding the biology of HIV-1 resistance to these agents and the ability to assess resistance based on changes within the envelope glycoprotein.The CCR5 coreceptor antagonists are unique in that they bind to the CCR5 coreceptor on the surface of the host cell, whereas most HIV-1 medicines interfere with virus propagation by inhibiting one of the essential virus-encoded enzymes. Signature mutations associated with resistance to HIV-1 reverse transcriptase, protease, and...

show abstract

Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5

Cited by 59 publications

References 51 publications

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer

Structure-Function Analysis of Human Immunodeficiency Virus Type 1 gp120 Amino Acid Mutations Associated with Resistance to the CCR5 Coreceptor Antagonist Vicriviroc

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