Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140

Tamamura, Hirokazu; Omagari, Akane; Hiramatsu, Ken; Gotoh, Kazuyo; Kanamoto, Taisei; Xu, Yao; Kodama, Eiichi; Matsuoka, Masao; Hattori, Toshio; Yamamoto, Naoki; Nakashima, Hideki; Otaka, Akira; Fujii, Nobutaka

doi:10.1016/s0960-894x(01)00323-7

Cited by 113 publications

(133 citation statements)

References 34 publications

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“…Understanding and modelling this process will not only elucidate new therapeutic targets but also may help to elaborate their mode of action. In addition, it will help to explore the potential therapeutic benefit of novel chemotherapeutic agents such as T140 (Tamamura et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…The effect of the specific CXCR4 inhibitor, T140 (Tamamura et al, 2001(Tamamura et al, , 2003, on prostate epithelial cell invasion was then assessed in the Matrigel invasion model with the PC-3 cell line ( Figure 6). The invasive stimulatory effect of the maximal invasive dose of SDF-1, 15 ng ml À1 (titration data not shown), was compared to the invasive stimuli from BMECs and primary BMS with or without 10 mg ml À1 T140 (concentration required to inhibit completely SDF-1 signalling in prostate epithelial cells (titration data not shown)).…”

Section: Inhibition Of Cxcr4 Signalling By T140mentioning

confidence: 99%

“…In this study, we have adapted existing bone marrow invasion models to represent the blood/BMS (BMS) barrier more closely and we have used these to follow malignant prostate epithelial invasion of the bone marrow compartment. Using these models, we have also evaluated the ability of the small peptide inhibitor of CXCR4, T140 (Tamamura et al, 2001) to inhibit prostatic invasion in vitro.…”

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confidence: 99%

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Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

et al. 2005

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Prostate cancer has a predilection to metastasise to the bone marrow stroma (BMS) by an as yet uncharacterised mechanism. We have defined a series of coculture models of invasion, which simulate the blood/BMS boundary and allow the elucidation of the signalling and mechanics of trans-endothelial migration within the complex bone marrow environment. Confocal microscopy shows that prostate epithelial cells bind specifically to bone marrow endothelial-to-endothelial cell junctions and initiate endothelial cell retraction. Trans-endothelial migration proceeds via an epithelial cell pseudopodial process, with complete epithelial migration occurring after 232743 min. Stromal-derived factor-1 (SDF-1)/CXCR4 signalling induced PC-3 to invade across a basement membrane although the level of invasion was 3.5-fold less than invasion towards BMS (P ¼ 0.0007) or bone marrow endothelial cells (P ¼ 0.004). Maximal SDF-1 signalling of invasion was completely inhibited by 10 mM of the SDF-1 inhibitor T140. However, 10 mM T140 only reduced invasion towards BMS and bone marrow endothelial cells by 59% (P ¼ 0.001) and 29% (P ¼ 0.011), respectively. This study highlights the need to examine the potential roles of signalling molecules and/or inhibitors, not just in single-cell models but in coculture models that mimic the complex environment of the bone marrow.

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Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Cxcr4 Signalling By T140mentioning

confidence: 99%

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confidence: 99%

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Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

et al. 2005

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“…A variety of antibodies, small molecular inhibitors and intracellular single-chain variable fragments (SFvs) have been used both in vitro, and some in vivo, to inhibit CXCR4-specific binding of HIV-1 in relevant target cells. [39][40][41][42][54][55][56][57][58][59][60] Of note, the in vivo-tested molecular inhibitors of CXCR4 did not appear to lead to significant adverse immunological effects. 42 In addition, targeting cellular proteins that act as cofactors in the HIV-1 life cycle may be of greater reliability than targeting viral mRNA species or genomic RNA with RNAi, as the propensity of this virus to undergo rapid mutations would alter the long-term inhibitory capabilities of siRNAs directed against the virus itself.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HIV-1 fusion with small interfering RNAs targeting the chemokine coreceptor CXCR4

et al. 2004

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RNA interference (RNAi) is an evolutionarily conserved process by which plants and animals protect their genomes utilizing small, double-stranded RNAs to degrade target RNAs in a sequence-specific manner. Post-transcriptional gene silencing by these moieties can lead to degradation of both cellular and viral RNAs. It has recently been shown that double-stranded, small interfering RNAs (siRNAs) of 21-25 nucleotides can be transfected into relevant cells to target specific RNAs. This approach was utilized to inhibit human immunodeficiency virus type I (HIV-1) infection in human cells. siRNAs with homology to a motif in the mRNA that encodes for the HIV-1 chemokine coreceptor CXCR4 was utilized. Complementary studies via immunofluorescence microscopy and fluorescence-activated cell sorting demonstrated downregulation of CXCR4 from the surface of cells transfected with the specific siRNAs. As well, siRNAs without sequence homology to CXCR4 were used as controls and demonstrated no downregulation of CXCR4. siRNAs targeted to another chemokine coreceptor, APJ, showed specificity for downregulation of APJ but had no effects on CXCR4.Transfections with siRNAs targeting CXCR4 mRNA were shown to inhibit HIV-1 envelope fusion, which is relatively resistant to most viral inhibitors targeting chemokine coreceptors. The specificity of this effect was demonstrated by the inhibition of fusion by CXCR4-tropic and dual-tropic (CXCR4 and CCR5) envelope glycoproteins from HIV-1 on CXCR4+ indicator cells, but the lack of effects by siRNAs targeting CXCR4 mRNA on dual-tropic HIV-1 envelopes in CCR5+ indicator cells utilizing these fusion assays. Interestingly, siRNAs targeting CXCR4 selectively inhibited CXCR4-tropic cell-free virus infection of human cells but at only modest levels as compared to cell:cell fusion. siRNA may be a potential molecular therapeutic approach to alter a cellular cofactor critical for infection of human cells by relevant strains of HIV-1. The targeting of a cellular cofactor, rather than the HIV-1-specific mRNAs or genomic RNA, holds promise as the rapid mutational ability of the HIV-1 genome may obviate the potential clinical use of RNAi directly against this virus.

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“…68 T140 is considered the most active CXCR4 peptide antagonist among the initially synthesized peptides, but lacks serum stability due to cleavage of the C-terminal Arg. Therefore, C-terminally amidated T140 analogs were developed to overcome serum instability, 70 leading to the synthesis of TN14003 and TC14012. Further work revealed the binding regions for T140 within the extracellular domains and regions of the hydrophobic core of CXCR4, which are distinct from the binding region for AMD3100.…”

Section: Small Peptide Antagonist Of Cxcr4mentioning

confidence: 99%

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Burger

Peled²

2008

Leukemia

416

316

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Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140

Cited by 113 publications

References 34 publications

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

Inhibition of HIV-1 fusion with small interfering RNAs targeting the chemokine coreceptor CXCR4

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

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