Computer-assisted rational design of immunosuppressive compounds

Grassy, G.; Calas, Bernard; Yasri, Abdelaziz; Lahana, Roger; Woo, Jacky; Iyer, Suhasini; Kaczorek, Michel; Floc'h, R.; Buelow, Roland

doi:10.1038/nbt0898-748

Cited by 95 publications

(64 citation statements)

References 23 publications

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“…We have previously reported that Allotrap 1258 modulates heme oxygenase activity in vitro and in vivo (8,12). In animals, peptide therapy resulted in up-regulation of heme oxygenase, and we have speculated that the immunomodulatory activity of Allotrap 1258 may be mediated via effects on HO-1.…”

Section: Discussionmentioning

confidence: 98%

“…In vivo, they were shown to prolong allograft survival in rodents (2)(3)(4)(5)(6)(7). Based on these HLA-derived peptide sequences, novel immunomodulatory peptides were developed by computer-aided rational design (8). Initially, the biological activity of a panel of 19 peptides derived from peptide 2702.75-84 (HLA-B2702, amino acids 75-84) as well as other major histocompatibility complex molecules was assessed in a heterotopic mouse allograft model.…”

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confidence: 99%

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Inhibition of Tumor Necrosis Factor mRNA Translation by a Rationally Designed Immunomodulatory Peptide

Iyer¹,

Kontoyiannis²,

Chevrier³

et al. 2000

Journal of Biological Chemistry

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Based on sequences of immunomodulatory peptides derived from the heavy chain of HLA Class I, novel immunomodulatory peptides with increased potency were developed by computer-aided rational design. Allotrap 1258 was characterized in detail and shown to inhibit cell-mediated immune responses in vitro and in vivo. Immunomodulatory activity was associated with the capability of the peptides to modulate heme oxygenase (HO) activity. In this study we analyzed the effect of Allotrap 1258 on cytokine expression. Allotrap 1258 inhibited concanavalin A-and lipopolysaccharide-induced human and mouse tumor necrosis factor (TNF) production in vitro and in vivo but had no effect on interleukin ( Peptides derived from the heavy chain of the HLA Class I molecule have been shown to modulate immune responses in vitro and in vivo (1-7). In vitro, these peptides inhibited cytotoxicity and differentiation of cytotoxic T cells (1). In vivo, they were shown to prolong allograft survival in rodents (2-7). Based on these HLA-derived peptide sequences, novel immunomodulatory peptides were developed by computer-aided rational design (8). Initially, the biological activity of a panel of 19 peptides derived from peptide 2702.75-84 (HLA-B2702, amino acids 75-84) as well as other major histocompatibility complex molecules was assessed in a heterotopic mouse allograft model. A rational drug design strategy based on these in vivo data resulted in a series of immunomodulatory peptides. One of these peptides, RDP1258 and its D-isomer, Allotrap 1258, showed enhanced efficacy in comparison with 2702.75-84 both in vivo when tested in rodent allograft models and in vitro in the inhibition of cytotoxicity in human and mouse T lymphocytes.The mechanism of immunomodulation mediated by these peptides is not fully understood. Observations in various in vivo models indicated that the peptides do not interact directly with T cell receptor or NK cell inhibitory receptors (4, 5, 9) The observation that both L-and D-isomers of peptide 2702.75-84 prolong graft survival indicates that the immunomodulatory activity of the peptides is not based on presentation by major histocompatibility complex molecules (5). Similarly, the recent hypothesis that these peptides modulate immune responses by binding to Hsc/Hsp70 can be excluded because the peptides D-enantiomers, while being immunomodulatory, do not bind to these proteins (10, 11). Affinity chromatography with one of these immunomodulatory peptides resulted in the identification of heme oxygenase-1 (HO-1) 1 as a potential target for these peptides (12). All of the biologically active peptides derived from 2702.75-84 were shown to inhibit HO activity in vitro. The original compounds, however, were 100-fold less potent than the rationally designed Allotrap 1258. Similar to what has been observed with other HO inhibitors, in vivo administration of the peptides to animals resulted in a rapid up-regulation of HO-1 protein expression (12). Subsequent studies with peptides and protoporphyrins specifically affecting HO ac...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Inhibition of Tumor Necrosis Factor mRNA Translation by a Rationally Designed Immunomodulatory Peptide

Iyer¹,

Kontoyiannis²,

Chevrier³

et al. 2000

Journal of Biological Chemistry

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“…In addition, a novel TNF-␣ inhibitor, RDP58 [131], was successfully used in our laboratory to treat acute and chronic Kollias, and R. Buelow, unpublished results]. RDP58 given orally or intraperitonealy at pharmacologically relevent doses reduced the severity of acute DSS-mediated colitis as judged from clinical and histological improvements.…”

Section: Relevancementioning

confidence: 99%

Insights from mouse models of colitis

Boismenu

Chen

2000

Journal of Leukocyte Biology

126

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Emerging studies using mouse models of experimental colitis are defining the nature of the immunological disturbances that initiate inflammation and destruction of the intestine. A better understanding of disease-promoting and -suppressing CD4 ؉ T cells is providing insight into the mechanisms controlling immune responses within the intestinal compartment. Moreover, a role for distinct T cell populations, including intraepithelial ␥␦ T cells, in maintaining the physical integrity of the intestine was suggested by recent studies. Cytokine gene-knockout mice and anti-cytokine treatments remain important tools to define the pro-and anti-inflammatory functions of cytokines. These advances are fostering the design and evaluation of new therapeutic approaches that may eventually be applied to treat human inflammatory bowel disease.

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“…For example, RDP58, a novel d-amino acid decapeptide (r-(nle)3-r-(nle)3-gy-CONH2), which was developed by computer-aided rational based design on human leukocyte antigen-derived peptides [177], has been discovered to suppress the T-helper 1 cytokine profile, decrease production of inflammatory cytokines including tumor necrosis factor-, interferon-, interleukin-2 and interleukin-12 in both cell lines and animal models [26,178,179]. Several clinical trials on human including phase I safety in normal volunteers, phase II mild-moderate active ulcerative colitis, phase II moderate active ulcerative colitis and phase IICrohn's disease had been completed (Genzyme Corporation; Sanofi, Bridgewater, NJ).…”

Section: Commercial Potential Of Milk Derived Proteins and Peptidesmentioning

confidence: 99%