Piperazine-Based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element

Tagat, Jayaram R.; McCombie, Stuart W.; Steensma, Ruo W.; Lin, Sue‐Ing; Nazareno, Dennis V.; Baroudy, Bahige M.; Vantuno, Nicole; Xu, Serena; Liu, Jia

doi:10.1016/s0960-894x(01)00381-x

Cited by 64 publications

(37 citation statements)

References 18 publications

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“…The CC101.19 escape mutant isolate is completely crossresistant to SCH-C (108), a small-molecule CCR5 inhibitor chemically related to AD101 (82,83,101,103,104,108). We therefore determined if the derived clones CC101.19 cl.3 and cl.7 were also cross-resistant.…”

Section: Resultsmentioning

confidence: 99%

Genetic and Phenotypic Analyses of Human Immunodeficiency Virus Type 1 Escape from a Small-Molecule CCR5 Inhibitor

Kuhmann

Pugach

Kunstman

et al. 2004

J Virol

187

218

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, Proc. Natl. Acad. Sci. USA 99:395-400, 2002). The escape mutant, CC101.19, continued to use CCR5 for entry, but it was at least 20,000-fold more resistant to AD101 than the parental virus, CC1/85. We have now cloned the env genes from the the parental and escape mutant isolates and made chimeric infectious molecular clones that fully recapitulate the phenotypes of the corresponding isolates. Sequence analysis of the evolution of the escape mutants suggested that the most relevant changes were likely to be in the V3 loop of the gp120 glycoprotein. We therefore made a series of mutant viruses and found that full AD101 resistance was conferred by four amino acid changes in V3. Each change individually caused partial resistance when they were introduced into the V3 loop of a CC1/85 clone, but their impact was dependent on the gp120 context in which they were made. We assume that these amino acid changes alter how the HIV-1 Env complex interacts with CCR5. Perhaps unexpectedly, given the complete dependence of the escape mutant on CCR5 for entry, monomeric gp120 proteins expressed from clones of the fully resistant isolate failed to bind to CCR5 on the surface of L1.2-CCR5 cells under conditions where gp120 proteins from the parental virus and a partially AD101-resistant virus bound strongly. Hence, the full impact of the V3 substitutions may only be apparent at the level of the native Env complex.Several members of a new class of inhibitors based on blocking human immunodeficiency virus type 1 (HIV-1) entry into target cells are now in, or approaching, human clinical trials (8,52,77,80,85,90,98). These various compounds antagonize different stages in the multistep pathway by which HIV-1 fuses with susceptible cells. For example, the CD4-immunoglobulin G2 protein (CD4-IgG2; PRO 542) attaches to the viral envelope glycoprotein gp120 to prevent it from interacting with the CD4 receptor (3, 109). The T-20 and T-1249 peptides act later, by inhibiting conformational changes in the viral gp41 glycoprotein that are necessary for membrane fusion to be initiated (8,40,72,115). All these inhibitors cause plasma viremia reductions in HIV-1-infected people (8,49,53,62,66,71,80).A step in the entry process intermediate between gp120-CD4 attachment and gp41 conformational changes involves a coreceptor for gp120 (21,31,37,85,98). Thus, after gp120 has bound to CD4, it changes conformation to enable it to bind to a coreceptor from the G-protein-coupled receptor superfamily (21,31,37,85,98,107,116). The most physiologically relevant coreceptors are the chemokine receptors CCR5 or CXCR4, the former used by HIV-1 strains that usually dominate early in infection and the latter used by viruses that sometimes emerge several years later or that are detectable only transiently (21,31,85,99,122). The presence of viruses able to use CXCR4 (X4 strains) is associated with an accelerated disease course, due in part to the loss of naive CD4 ϩ T cells that express CXCR4 but not CCR5 (32,44,69). Viruses using CCR5 (R5 strains) target memory CD4 ϩ...

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Section: Resultsmentioning

confidence: 99%

Genetic and Phenotypic Analyses of Human Immunodeficiency Virus Type 1 Escape from a Small-Molecule CCR5 Inhibitor

Kuhmann

Pugach

Kunstman

et al. 2004

J Virol

187

218

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“…SCH-C and AD101, an earlier-generation compound from the same chemical family of piperidine-based molecules, have been studied as model CCR5 inhibitors (37,48,49,63,(66)(67)(68)(69)(70). AD101 is more potent than SCH-C as an HIV-1 entry inhibitor in vitro, but its unfavorable pharmacological properties have prevented it from being pursued as a clinical candidate.…”

Section: Resultsmentioning

confidence: 99%

The Differential Sensitivity of Human and Rhesus Macaque CCR5 to Small-Molecule Inhibitors of Human Immunodeficiency Virus Type 1 Entry Is Explained by a Single Amino Acid Difference and Suggests a Mechanism of Action for These Inhibitors

Billick

Seibert

Pugach

et al. 2004

J Virol

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AD101 and SCH-C are two chemically related small molecules that inhibit the entry of human immunodeficiency virus type 1 (HIV-1) via human CCR5. AD101 also inhibits HIV-1 entry via rhesus macaque CCR5, but SCH-C does not. Among the eight residues that differ between the human and macaque versions of the coreceptor, only one, methionine-198, accounts for the insensitivity of macaque CCR5 to inhibition by SCH-C. Thus, the macaque coreceptor engineered to contain the natural human CCR5 residue (isoleucine) at position 198 is sensitive to HIV-1 entry inhibition by SCH-C, whereas a human CCR5 mutant containing the corresponding macaque residue (methionine) is resistant. Position 198 is in CCR5 transmembrane (TM) helix 5 and is not located within the previously defined binding site for AD101 and SCH-C, which involves residues in TM helices 1, 2, 3, and 7. SCH-C binds to human CCR5 whether residue 198 is isoleucine or methionine, and it also binds to macaque CCR5. However, the binding of a conformation-dependent monoclonal antibody to human CCR5 is inhibited by SCH-C only when residue 198 is isoleucine. These observations, taken together, suggest that the antiviral effects of SCH-C and AD101 involve stabilization, or induction, of a CCR5 conformation that is not compatible with HIV-1 infection. However, SCH-C is unable to exert this effect on CCR5 conformation when residue 198 is methionine. The region of CCR5 near residue 198 has, therefore, an important influence on the conformational state of this receptor.

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“…The chemical syntheses of SCH-C (SCH 351125) and vicriviroc (SCH-D, or SCH 417690) have been previously described (17,22,23) The CCR5-tropic clinical HIV-1 isolate R5-01 used for the drug combination studies was derived from a subject with acute HIV-1 primary infection syndrome at the Massachusetts General Hospital.…”

Section: Methodsmentioning

confidence: 99%

Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

Strizki¹,

Tremblay

Xu³

et al. 2005

Antimicrob Agents Chemother

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200

115

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Piperazine-Based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element

Cited by 64 publications

References 18 publications

Genetic and Phenotypic Analyses of Human Immunodeficiency Virus Type 1 Escape from a Small-Molecule CCR5 Inhibitor

Genetic and Phenotypic Analyses of Human Immunodeficiency Virus Type 1 Escape from a Small-Molecule CCR5 Inhibitor

The Differential Sensitivity of Human and Rhesus Macaque CCR5 to Small-Molecule Inhibitors of Human Immunodeficiency Virus Type 1 Entry Is Explained by a Single Amino Acid Difference and Suggests a Mechanism of Action for These Inhibitors

Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

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