Therapeutic peptidomimetic strategies for autoimmune diseases: costimulation blockade*

Allen, Stephanie D.; Rawale, Sharad; Cc, Whitacre; Kaumaya, Pravin T. P.

doi:10.1111/j.1399-3011.2005.00256.x

Cited by 44 publications

(52 citation statements)

References 123 publications

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“…However, if direct ligation of platelet CD154, not just FcR binding, is responsible for certain complications, this drawback will remain. Peptidomimetics can also provide a way to block CD40-CD154 interactions (49). However, peptide-binding affinities can frequently be modest, requiring large and potentially impractical quantities to effectively compete with CD154 for CD40 binding.…”

Section: Discussionmentioning

confidence: 99%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes.

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Section: Discussionmentioning

confidence: 99%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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“…Peptidomimetics are also water-soluble and are non-immunogenic. This allows them to be administered for longer periods of time [65]. It, therefore, seems possible to speculate that peptidomimetics may be useful in future therapies that need to modulate proteinprotein interactions, and in the case of sepsis, activate anti-apoptotic proteins, which may protect those cells from apoptosis normally lost during the course of the disease.…”

Section: Apoptotic Targets and Therapeutic Considerations Targeting Tmentioning

confidence: 99%

The Apoptotic Pathway as a Therapeutic Target in Sepsis

Wesche-Soldato¹,

Swan²,

Chung³

et al. 2007

CDT

138

114

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Recent research has yielded many interesting and potentially important therapeutic targets in sepsis. Specifically, the effects of antagonistic anti-cytokine therapies (tumor necrosis factor-alpha [TNF-α], interleukin-1 [IL-1]) and anti-endotoxin strategies utilizing antibodies against endotoxin or endotoxin receptor/carrier molecules (anti-CD14 or anti-LPS-binding protein) have been studied. Unfortunately, these approaches often failed clinically, and in many cases, the efficacy of these treatments was dependent on the severity of sepsis. Recently, clinical trials using insulin to lock blood glucose levels and activated protein C treatment have showed that while they provided some survival benefit, their efficacy does not appear to be predicated solely upon anti-inflammatory effects. Here, we will review work done in animal models of polymicrobial sepsis and clinical findings that support the hypothesis that apoptosis in the immune system is a pathologic event in sepsis that can be a therapeutic target. In this respect, experimental studies looking at the septic animal suggest that loss of lymphocytes during sepsis may be due to dysregulated apoptosis and that this appears to be brought on by a variety of mediators effecting 'intrinsic' as well as 'extrinsic' cell death pathways. From a therapeutic perspective this has provided a number of novel targets for clinically successful current, as well as future therapies, such as caspases (caspase inhibition/protease inhibition), pro-apoptotic protein-expression (via administration and/or over-expression of Bcl-2) and the death receptor family Fas-FasL (via. FasFP [fas fusion protein] and the application of siRNA against a number proapoptotic factors).

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“…Previous data revealed that the peptidomimetic is water soluble and nonimmunogenic (64). In comparison with Smac, Smac mimetic could cross the cell membrane and bind efficiently to its target proteins (65).…”

Section: Targeting Livin By Blocking Protein Functionmentioning

confidence: 99%

Challenge and promise: roles for Livin in progression and therapy of cancer

Wang

Zhang²,

Liu

et al. 2008

Molecular Cancer Therapeutics

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Livin is a member of the inhibitors of apoptosis protein gene family, which is highly expressed in a variety of human neoplasms. Several studies have shown that down-regulation of Livin expression increases the apoptotic rate, reduces tumor growth potential, and sensitizes tumor cells to chemotherapeutic drugs. Furthermore, emerging data reveal that Livin fragments cleavaged by caspases restored paradoxical proapoptotic activity during the apoptotic process, suggesting that Livin cleavage will become a highly potent proapoptotic agent in the future. In this article, we review the current understanding of the versatile roles of Livin in the apoptotic cascade and exploit the promising approach to interfere with Livin as a novel strategy for cancer therapy. [Mol Cancer Ther 2008;7(12):3661 -9]

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Therapeutic peptidomimetic strategies for autoimmune diseases: costimulation blockade*

Cited by 44 publications

References 123 publications

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

The Apoptotic Pathway as a Therapeutic Target in Sepsis

Challenge and promise: roles for Livin in progression and therapy of cancer

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