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

Seibert, Christoph; Ying, Weiwen; Gavrilov, Svetlana; Tsamis, Fotini; Kuhmann, Shawn E.; Palani, Anandan; Tagat, Jayaram R.; Clader, John W.; McCombie, Stuart W.; Baroudy, Bahige M.; Smith, Steven O.; Dragic, Tatjana; Moore, John P.; Sakmar, Thomas P.

doi:10.1016/j.virol.2006.01.018

Cited by 115 publications

(118 citation statements)

References 75 publications

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“…Note that an Ile-Met change at position 189 in TM5 indirectly compromises the antiviral activity of a different CCR5 inhibitor, SCH-C, again without this residue being part of the inhibitor-binding site (48). Another probable long-range effect on the CCR5 structure involves the T82A substitution, which partially impairs the inhibitory activity of TAK779 but not that of other small molecules, including AD101 and SCH-C (7,27). Overall, the two changes at residue 82 that create the CCR5-T82K and CCR5-T82P CAMs have different effects on VVC and MVC binding and HIV-1 entry, presumably because they alter the overall geometry of CCR5 in different ways that are not yet understood at the molecular level.…”

Section: Discussionmentioning

confidence: 99%

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Berro

Yasmeen

Abrol

et al. 2013

J Virol

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Small-molecule CCR5 inhibitors such as vicriviroc (VVC) and maraviroc (MVC) are allosteric modulators that impair HIV-1 entry by stabilizing a CCR5 conformation that the virus recognizes inefficiently. Viruses resistant to these compounds are able to bind the inhibitor-CCR5 complex while also interacting with the free coreceptor. CCR5 also interacts intracellularly with G proteins, as part of its signal transduction functions, and this process alters its conformation. Here we investigated whether the action of VVC against inhibitor-sensitive and -resistant viruses is affected by whether or not CCR5 is coupled to G proteins such as G␣ i . Treating CD4 ؉ T cells with pertussis toxin to uncouple the G␣ i subunit from CCR5 increased the potency of VVC against the sensitive viruses and revealed that VVC-resistant viruses use the inhibitor-bound form of G␣ i -coupled CCR5 more efficiently than they use uncoupled CCR5. Supportive evidence was obtained by expressing a signaling-deficient CCR5 mutant with an impaired ability to bind to G proteins, as well as two constitutively active mutants that activate G proteins in the absence of external stimuli. The implication of these various studies is that the association of intracellular domains of CCR5 with the signaling machinery affects the conformation of the external and transmembrane domains and how they interact with small-molecule inhibitors of HIV-1 entry.

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Section: Discussionmentioning

confidence: 99%

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Berro

Yasmeen

Abrol

et al. 2013

J Virol

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“…This resistance pathway often, but not always, results in a virus that is resistant to multiple CCR5 antagonists (22,33,39,53,56). The CCR5 antagonists that have been used clinically all seem to bind to a hydrophobic region in the transmembrane helices of CCR5 and induce conformational alterations in the extracellular domains of the coreceptor that inhibit recognition by gp120 (13,31,32,46,52). These conformational alterations are similar though not identical as judged by the ability of these compounds to affect the binding of various conformation-dependent monoclonal antibodies to CCR5.…”

Section: Discussionmentioning

confidence: 99%

“…Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sulfated tyrosine residues in the NЈ terminus of CCR5, and (ii) the crown of the V3 loop is thought to engage the extracellular loops (ECLs), particularly ECL2, of CCR5 (10-12, 14, 18, 28). Small-molecule CCR5 antagonists bind to a hydrophobic pocket in the transmembrane helices of CCR5 and exert their effects on HIV by altering the position of the ECLs, making them allosteric inhibitors of HIV infection (13,31,32,46,52). The conformational changes in CCR5 that are induced by CCR5 antagonists vary to some degree with different drugs, as evidenced by differential binding of antibodies and chemokines to various drug-bound forms of CCR5 (47,54).…”

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confidence: 99%

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Pfaff

Wilen

Harrison

et al. 2010

J Virol

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We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4 ؉ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a Entry of human immunodeficiency virus (HIV) into target cells is a complex, multistep process that is initiated by interactions between the viral envelope (Env) protein gp120 and the host cell receptor CD4, which trigger conformational changes in gp120 that form and orient the coreceptor binding site (9,24). Upon binding to coreceptor, which is either CCR5 or CXCR4 for primary HIV isolates, Env undergoes further conformational changes resulting in insertion of the gp41 fusion peptide into the host cell membrane and gp41-mediated membrane fusion (8,15,26). Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-

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“…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%

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

Kondru

Zhang²,

Ji³

et al. 2007

Mol Pharmacol

172

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

Cited by 115 publications

References 75 publications

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

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

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

Cited by 115 publications

References 75 publications

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

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

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Product

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HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells