Molecular‐Size Reduction of a Potent CXCR4‐Chemokine Antagonist Using Orthogonal Combination of Conformation‐ and Sequence‐Based Libraries

Fujii, Nobutaka; Oishi, Shinya; Hiramatsu, Ken; Araki, Takanobu; Ueda, Satoshi; Tamamura, Hirokazu; Otaka, Akira; Kusano, Shuichi; Terakubo, Shigemi; Nakashima, Hideki; Broach, James R.; Trent, John O.; Wang, Zi Xuan; Peiper, Stephen C.

doi:10.1002/anie.200351024

Cited by 193 publications

(134 citation statements)

References 17 publications

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“…Attempts to develop small cyclic peptide and nonpeptide analogs from T140 (12,36,37) have pointed to the importance of both a guanide functional group (in the form of an arginine side chain) and an aromatic group (napthyl). This is consistent with our observation that the phenylguanides were more active than either the guanides or the biguanides and suggests that using a larger aromatic moiety such as naphthalene may increase the observed CXCR4 binding compared to our initial phenylguanide derivatives.…”

mentioning

confidence: 99%

Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

Wilkinson

Pincus

Shepard

et al. 2011

Antimicrob Agents Chemother

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The G-protein-coupled receptor CXCR4 acts as a coreceptor for human immunodeficiency virus type 1 (HIV-1) infection, as well as being involved in signaling cell migration and proliferation. Compounds that block CXCR4 interactions have potential uses as HIV entry inhibitors to complement drugs such as maraviroc that block the alternate coreceptor CCR5 or in cancer therapy. The peptide T140, which contains five arginine residues, is the most potent antagonist of CXCR4 developed to date. In a search for nonpeptide CXCR4 ligands that could inhibit HIV entry, three series of compounds were synthesized from 12 linear and branched polyamines with 2, 3, 4, 6, or 8 amino groups, which were substituted to produce the corresponding guanidines, biguanides, or phenylguanides. The resulting compounds were tested for their ability to compete with T140 for binding to the human CXCR4 receptor expressed on mammalian cells. The most effective compounds bound CXCR4 with a 50% inhibitory concentration of 200 nM, and all of the compounds had very low cytotoxicity. Two series of compounds were then tested for their ability to inhibit the infection of TZM-bl cells with X4 and R5 strains of HIV-1. Spermine phenylguanide and spermidine phenylguanide inhibited infection by X4 strains, but not by R5 strains, at low micromolar concentrations. These results support further investigation and development of these compounds as HIV entry inhibitors.

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mentioning

confidence: 99%

Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

Wilkinson

Pincus

Shepard

et al. 2011

Antimicrob Agents Chemother

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“…Thus, this key paper [49] demonstrated the simultaneous importance of sequence, stereochemistry, and cyclic constraint for CXCR4 antagonism, and also revealed the presumed bioactive backbone conformation for the lead cyclopentapeptide antagonist FC131.…”

Section: Discovery Of the Cyclopentapeptide Cxcr4 Antagonistsmentioning

confidence: 75%

“…The cyclopentapeptide antagonists [49] ( Figure 5A) were developed from the macrocyclic 14--mer polypeptide lead compound T140 ( Figure 1A) [40], and the downsizing strategy was based on combining the four pharmacophoric residues of T140 (Arg 2 , 2--Nal 3 A solution structure for FC131 based on 1 H--NMR studies in DMSO was also reported [49]. While the exact spatial orientation of the relatively flexible side chains could not be determined, the reported backbone conformation is consistent with later NMR studies of the bioactive (receptor--bound)…”

Section: Discovery Of the Cyclopentapeptide Cxcr4 Antagonistsmentioning

confidence: 99%

“…In addition to the "conformation--based" and "sequence--based" libraries in the original paper [49], biological data were soon reported for a third cyclopentapeptide library, consisting of retro--inverso analogs ( Figure 5B) [92]. However, the retro--inverso analog with highest potency (EC50 = 1.7 μM) was 19--fold less potent than FC131 (EC50 = 0.088 μM).…”

Section: Backbone Modificationsmentioning

confidence: 99%

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Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

Våbenø

Haug

2015

Future Med. Chem.

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Over the last five years, X--ray structures of CXC chemokine receptor 4 (CXCR4) in complex with three different ligands (the small--molecule antagonist IT1t, the polypeptide antagonist CVX15, and the viral chemokine antagonist vMIP--II) have been released. In addition to the inherent scientific value of these specific X--ray structures, they (i) provide a reliable structural foundation for studies of the molecular interactions between CXCR4 and its key peptide ligands (CXCL12 and HIV--1 gp120); and (ii) serve as valuable templates for further development of small--molecule CXCR4 antagonists with therapeutic potential. We here review recent computational studies of the molecular interactions between CXCR4 and its peptide ligands -based on the X--ray structures of CXCR4 -and the current status of small--molecule peptide and peptidomimetic CXCR4 antagonists. 2) Isostere: In the context of this review, an isostere is defined as any functional group or moiety that is included in a peptide sequence as a replacement of an amide bond.3) Scaffold: The term scaffold is used for rigid (normally cyclic) structures onto which the functional groups of amino acid side chains can be introduced. 4) Structure--based and ligand--based design:In structure--based design, the 3D structure of the target is known and guides the design of active compounds. When the 3D structure of the target is unknown, indirect information has to be used in order to design/optimize compounds that bind to the target. This information is normally obtained through SAR studies and pharmacophore modeling, and the overall approach is known as ligand--based design. 5) 7TM receptors: As signalling via G proteins is a common feature for seven--

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“…In the development of these assays, we profiled a set of four CXCR4 antagonists (AMD3100, T140, FC131, and CTCE-9908) [16][17][18][19][20] and phorbol 12-myristate 13-acetate (PMA), a potent protein kinase C (PKC) activator. 21 A screening campaign was subsequently performed with a 30,000-compound library (constituted of commercial and proprietary compounds selected to maximize chemical diversity); a homogeneous time-resolved fluorescence (HTRF) assay to measure Gα i -mediated changes in intracellular cAMP levels was used as a primary screen, and β-arrestin recruitment and receptor internalization as secondary assays.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 Antagonists: A Screening Strategy for Identification of Functionally Selective Ligands

et al. 2014

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The CXC chemokine receptor 4 (CXCR4) is a widely expressed G protein-coupled receptor implicated in several diseases. In cancer, an increased number of surface CXCR4 receptors, in parallel with aberrant signaling, have been reported to influence several aspects of malignancy progression. CXCR4 activation by the specific ligand C-X-C motif chemokine 12 (CXCL12) induces several intracellular signaling pathways that have been selectively related to malignancy depending on the tissue or cell type. We developed a panel of CXCR4 screening assays investigating Gα i -mediated cyclic adenosine monophosphate modulation, β-arrestin recruitment, and receptor internalization. All of the assays were set up in recombinant cells and were used to test four reported CXCR4 antagonists. Consequently, a set of hit compounds, deriving from a screening campaign of a 30,000-small-molecule internal library, was profiled with the different assays. We identified several compounds showing a pathway-selective activity: antagonists on a Gα i -dependent pathway; antagonists on both the β-arrestin and Gα i -dependent pathways, some of which induce receptor internalization; and compounds with an antagonist behavior in all of the readouts. The identified biased antagonists induce different functional states on CXCR4 and preferentially affect specific downstream responses from the activated receptor, thus providing an improved therapeutic profile for correction of CXCR4 abnormal signaling.

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Molecular‐Size Reduction of a Potent CXCR4‐Chemokine Antagonist Using Orthogonal Combination of Conformation‐ and Sequence‐Based Libraries

Cited by 193 publications

References 17 publications

Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

CXCR4 Antagonists: A Screening Strategy for Identification of Functionally Selective Ligands

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