Synthesis of Peptides Mimicking Chemokine Receptor CCR5 and Their Inhibitory Effects against HIV-1 Infection.

Konishi, Koji; Ikeda, Kiyoshi; Achiwa, Kazuo; Hoshino, Hiroo; Tanaka, Kiyoshi

doi:10.1248/cpb.48.308

Cited by 5 publications

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“…In the studies presented here, the synthetic peptide approach previously used to analyze the N-terminal [14][15][16]36,37 and transmembrane 38 regions of CCR5 has been extended to the ECLs. We demonstrate that synthetic peptides derived from each of the CCR5 ECLs can block the fusogenic activity of HIV-1 Env and that the inhibition patterns vary for different Envs.…”

Section: Discussionmentioning

confidence: 99%

Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5

Agrawal

VanHorn-Ali

Berger

et al. 2004

Blood

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We used synthetic peptides to the extracellular loops (ECLs) of CCR5 to examine inhibitory effects on HIV infection/fusion with primary leukocytes and cells expressing recombinant CCR5. We show for the first time that peptides derived from the first, second, or third ECL caused dose-dependent inhibition of fusion and infection, although with varying potencies and specificities for envelope glycoproteins (Envs) from different strains. The first and third ECL peptides inhibited Envs from the R5 Ba-L strain and the R5X4 89.6 strain, whereas the second ECL peptide inhibited Ba-L but not 89.6 Env. None of the peptides affected fusion mediated by Env from the X4 LAV strain. IntroductionInfection by HIV-1 requires surface expression of 2 specific receptors on the target cell: CD4 (the primary receptor) and a specific chemokine receptor (the coreceptor). In the generally accepted model for HIV-1 entry (for reviews, see Wyatt and Sodroski 1 and Eckert and Kim 2 ), the external glycoprotein (gp) 120 subunit of the HIV-1 envelope glycoprotein (Env) initiates infection through specific binding to the first domain of CD4. The CD4 interaction induces a conformational change that exposes a highly conserved coreceptor binding site on gp120, which, along with variable loops on gp120, enables gp120 to bind to the coreceptor. The gp120-coreceptor interaction then triggers conformational changes in the gp41 transmembrane subunit of Env, presumably leading to exposure of the N-terminal fusion peptide and its insertion into the plasma membrane of the target cell to initiate the membrane fusion process.Individual HIV-1 isolates can display markedly distinct phenotypes for infection of different CD4-expressing cell types such as primary macrophages, transformed T-cell lines, or primary T cells. Target cell tropism is determined primarily by the ability of the corresponding Env to interact with one or both of the major coreceptors (CCR5, CXCR4), coupled with the expression patterns of these receptor molecules on the different target cell types (for a review, see Berger et al 3 ). HIV-1 isolates capable of using CCR5 but not CXCR4 (designated R5) 4-8 are typically macrophage tropic and greatly predominate after acute infection and throughout the asymptomatic phase. Isolates able to use CXCR4 9 are first detected during the transition to the symptomatic phase; those that function with CXCR4 but not CCR5 (designated X4) are typically T-cell line tropic, whereas those able to function with both coreceptors (designated R5X4) are dual tropic. All these HIV-1 phenotypes readily infected activated primary CD4 ϩ T cells. The gp120/ corecptor interaction has become a major focus for the development of new anti-HIV agents for treating or preventing HIV-1 infection (for reviews, see Agrawal and Alkhatib 10 and Biscone et al 11 ).The coreceptors are members of the superfamily of G-proteincoupled receptors (GPCRs). These proteins are characterized by 7 transmembrane segments that form a helical bundle, an extracellular region that includes the N-ter...

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Section: Discussionmentioning

confidence: 99%

Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5

Agrawal

VanHorn-Ali

Berger

et al. 2004

Blood

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“…They also facilitated determination of high-resolution structures of CCR5 N terminus peptides in complex with gp120, furthering our understanding of this interaction at an atomic level (19,20) and making possible the discovery of small molecule CCR5 N terminus mimetics (21). Such studies demonstrate the value in using peptide fragments of G protein-coupled receptors as tools to study coreceptor interactions because appropriate peptides tend to function in part as coreceptor mimics (22,23).…”

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confidence: 99%

Peptides from Second Extracellular Loop of C-C Chemokine Receptor Type 5 (CCR5) Inhibit Diverse Strains of HIV-1

Dogo‐Isonagie

Lam

Gustchina

et al. 2012

Journal of Biological Chemistry

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Background: Extracellular regions ECL2 and the N terminus of HIV coreceptor CCR5 mediate HIV-1 entry. Results: A C-terminal CCR5 ECL2 peptide inhibits HIV-1 entry and binds to gp120 of CCR5-and CXCR4-using strains. Conclusion: The binding site for CCR5 ECL2 is conserved in CCR5-and CXCR4-using viruses. Significance: Our data provide new insights into HIV-1 gp120-CCR5 interactions that can be used for inhibitor design.

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“…12) We designed compounds with non-peptide spacers such as a benzene ring in place of the Ala-Ala-Ala sequence of the peptide moiety of CCR5. As part of a program aimed at the development of new HIV-1 inhibitors, [13][14][15][16][17][18] we would like to report the design and synthesis of CCR5 peptide mimics derived from the first extracellular loop of CCR5 bearing non-peptide spacers in place of AlaAla-Ala sequence in the peptide moiety for prevention of HIV-1 infection based on a strategy of binding to gp120.…”

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confidence: 99%

Synthesis and Biological Evaluation of Peptide Mimics Derived from First Extracellular Loop of CCR5 toward HIV-1

Ikeda

Ishii

Konishi

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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The chemokine receptor CCR5, a member of the seventransmembrane G-protein coupled family of receptors, 1) has been identified as a primary co-receptor with CD4 by which macrophage tropic human immunodeficiency virus type-1 (HIV-1) strains infect their host cells.2) Since the discovery of CCR5 as a co-receptor with CD4 for HIV-1 cell entry, there has been interest in discovering small molecule CCR5 antagonists [3][4][5][6] as well as CXCR4 antagonists 7) and HIV-1 protease inhibitors 8) as potential agents for the treatment of HIV-1 infection.The entry of HIV-1 to cells involves the binding of the trimeric viral envelope glycoprotein gp120/gp41 to cell surface receptor CD4 and chemokine co-receptor CXCR4 or CCR5, which triggers conformational changes in the envelope proteins. Gp120 then dissociates from gp41, allowing for the fusion peptides to be inserted into the target membrane and the pre-hairpin configuration of the ectodomain to form.9-11) Regulation of CCR5 number on cells is important in determining the infection rate by HIV-1. Therefore, CCR5 is a highly valued target for the treatment of HIV-1 infection.It was demonstrated that the Gly-Gly-Gly sequence of the peptide moiety in lipopeptides could be replaced with a nonpeptide spacer.12) We designed compounds with non-peptide spacers such as a benzene ring in place of the Ala-Ala-Ala sequence of the peptide moiety of CCR5. As part of a program aimed at the development of new HIV-1 inhibitors, [13][14][15][16][17][18] we would like to report the design and synthesis of CCR5 peptide mimics derived from the first extracellular loop of CCR5 bearing non-peptide spacers in place of AlaAla-Ala sequence in the peptide moiety for prevention of HIV-1 infection based on a strategy of binding to gp120. Results and DiscussionIn the amino acid sequence of the N-terminal domain of CCR5, we chose the region of Tyr 89 -Gly 97 including alanine tripeptide. The peptide of natural type peptide 1 and its mimicking peptides 2a-c consisting of unnatural-type amino acids derived from aminophenol as the spacer unit were prepared. First, the nona-peptide 1 was synthesized manually by a stepwise liquid-phase procedure. The synthesis of 2a-c is shown in Chart 2. Aminophenoxyacetates 3a-c as spacers were prepared from the corresponding nitrophenols and tertbutyl bromoacetate. 19,20) Coupling of compounds 3a-c with 9-fluorenylmethoxycarbonyl (Fmoc)-Tyr(Bn) in the presence of 1-benzotriazoyloxy-tris-dimethylaminophosphonium hexafluorophosphate (BOP) and 1-hydroxy-1H-benzotriazole (HOBt) in N,N-dimethylformamide (DMF) gave compounds 4a-c in 72%, 73% and 86% yield, respectively. The deprotection of tert-butyl group of 4a-c with trifluoroacetic acid (TFA) afforded compounds 5a, 5b, and 5c in 71%, quant. and 93% yield, respectively. Compounds 5a-c were coupled with penta-peptide 6 in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and HOBt in DMF to give compounds 7a-c in 78%, 81% and 95% yield, respectively. Finally, hydrogenolysis of compounds 7a-c cata...

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Synthesis of Peptides Mimicking Chemokine Receptor CCR5 and Their Inhibitory Effects against HIV-1 Infection.

Cited by 5 publications

References 0 publications

Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5

Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5

Peptides from Second Extracellular Loop of C-C Chemokine Receptor Type 5 (CCR5) Inhibit Diverse Strains of HIV-1

Synthesis and Biological Evaluation of Peptide Mimics Derived from First Extracellular Loop of CCR5 toward HIV-1

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