Blocking peptides and molecular mimicry as treatment for kidney disease

Havasi, Andrea; Lu, Weining; Cohen, Herbert T.; Beck, Laurence H.; Wang, Zhiyong; Igwebuike, Chinaemare; Borkan, Steven C.

doi:10.1152/ajprenal.00601.2015

Cited by 6 publications

(5 citation statements)

References 75 publications

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“…Blocking peptides competitively inhibit protein-protein interactions by mimicking the binding domains. 31 As for monoclonal antibodies, blocking peptides are characterized by a high specificity and high affinity, but are much smaller. Their amino acid sequence is derived from a natural protein and unlikely to cause an immune response or loss of efficacy over time.…”

Section: Discussionmentioning

confidence: 99%

Peptide Blocking Self-Polymerization of Extracellular Calcium-Sensing Receptor Attenuates Hypoxia-Induced Pulmonary Hypertension

et al. 2021

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Activation of the CaSR (extracellular calcium-sensing receptor) has been recognized as a critical mediator of hypoxia-induced pulmonary hypertension. Preventive targeting of the early initiating phase as well as downstream events after CaSR activation remains unexplored. As a representative of the G protein-coupled receptor family, CaSR polymerizes on cell surface upon stimulation. Immunoblotting together with MAL-PEG technique identified a reactive oxygen species-sensitive CaSR polymerization through its extracellular domain in pulmonary artery smooth muscle cells upon exposure to acute hypoxia. Fluorescence resonance energy transfer screening employing blocking peptides determined that cycteine129/131 residues in the extracellular domain of CaSR formed intermolecular disulfide bonds to promote CaSR polymerization. The monitoring of intracellular Ca 2+ signal highlighted the pivotal role of CaSR polymerization in its activation. In contrast, the blockade of disulfide bonds formation using a peptide decreased both CaSR and hypoxia-induced mitogenic factor expression as well as other hypoxic-related genes in vitro and in vivo and attenuated pulmonary hypertension development in rats. The blocking peptide did not affect systemic arterial oxygenation in vivo but inhibited acute hypoxia-induced pulmonary vasoconstriction. Pharmacokinetic analyses revealed a more efficient lung delivery of peptide by inhaled nebulizer compared to intravenous injection. In addition, the blocking peptide did not affect systemic arterial pressure, body weight, left ventricular function, liver, or kidney function or plasma Ca 2+ level. In conclusion, a peptide blocking CaSR polymerization reduces its hypoxia-induced activation and downstream events leading to pulmonary hypertension and represents an attractive inhaled preventive alternative worthy of further development.

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Section: Discussionmentioning

confidence: 99%

Peptide Blocking Self-Polymerization of Extracellular Calcium-Sensing Receptor Attenuates Hypoxia-Induced Pulmonary Hypertension

et al. 2021

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“…Small interfering peptides that target protein-protein interactions are attracting increasing attention as potential therapeutics, partly due to their high binding specificity and affinity, and minimal off-target effects (Fosgerau and Hoffmann, 2015 ; Havasi et al, 2017 ). Interfering peptides targeting AMPAR endocytosis were shown effective in preventing the expression of D-amphetamine-induced behavioral sensitization and facilitating the extinction of morphine-induced conditioned place preference in rodent models of drug addiction (Brebner et al, 2005 ; Dias et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…We propose that peptides disrupting the diffusion trapping mechanism of AMPARs are an alternative strategy. Though promising, the therapeutic application of cell-penetrating peptides in humans remains challenging (Fosgerau and Hoffmann, 2015 ; Havasi et al, 2017 ). As an alternative, aptamers are oligonucleotide molecules that bind to a specific target molecule.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional Dysregulation of AMPA Receptor-Mediated Synaptic Transmission and Plasticity in Brain Disorders

Zhang

Bramham

2020

Front. Synaptic Neurosci.

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AMPA receptors (AMPARs) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission throughout the brain. Changes in the properties and postsynaptic abundance of AMPARs are pivotal mechanisms in synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. A wide range of neurodegenerative, neurodevelopmental and neuropsychiatric disorders, despite their extremely diverse etiology, pathogenesis and symptoms, exhibit brain region-specific and AMPAR subunit-specific aberrations in synaptic transmission or plasticity. These include abnormally enhanced or reduced AMPAR-mediated synaptic transmission or plasticity. Bidirectional reversal of these changes by targeting AMPAR subunits or trafficking ameliorates drug-seeking behavior, chronic pain, epileptic seizures, or cognitive deficits. This indicates that bidirectional dysregulation of AMPAR-mediated synaptic transmission or plasticity may contribute to the expression of many brain disorders and therefore serve as a therapeutic target. Here, we provide a synopsis of bidirectional AMPAR dysregulation in animal models of brain disorders and review the preclinical evidence on the therapeutic targeting of AMPARs.

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“…Both exogenous and endogenous molecules such as HSPs can induce cytokine secretion following their interaction with these extracellular receptors [ 27 , 33 , 34 , 35 , 36 , 37 ]. Blocking peptides are used in this study because they competitively block protein–protein interaction, by mimicking protein‐specific binding sites [ 38 ]. Therefore, blocking peptides can bind specific receptors following incubation with cells.…”

Section: Methodsmentioning

confidence: 99%

Exogenous heat shock proteins HSPA1A and HSPB1 regulate TNF‐α, IL‐1β and IL‐10 secretion from monocytic cells

Ogbodo

Michelangeli

Williams³

2023

FEBS Open Bio

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Endogenous molecules, such as heat shock proteins (HSP), can function as danger signals when released into the extracellular environment in response to cell stress, where they elicit an immune response such as cytokine secretion. There has also been some suggestion that contamination of exogenous HSPs with lipopolysaccharide (LPS) may be responsible for these effects. This study investigates the effects of exogenous HSPA1A and HSPB1 on the activation of immune cells and the resulting secretion of cytokines, which are involved in inflammatory responses. To address whether exogenous HSPs can directly activate cytokine secretion, naïve U937 cells, differentiated U937 cells, and peripheral blood mononuclear cells (PBMCs) were treated with either exogenously applied HSPA1A or HSPB1, and then secreted IL‐1β, TNF‐α, and IL‐10 were measured by ELISA. Both HSPs were able to induce a dose‐dependent increase in IL‐10 secretion from naïve U937 cells and dose‐dependent IL‐1β, TNF‐α and IL‐10 secretion were also observed in differentiated U937 cells and PBMCs. We also observed that CD14 affects the secretion levels of IL‐1β, TNF‐α, and IL‐10 from cells in response to exogenous HSP treatment. In addition, HSPA1A and HSPB1 were shown to interact with CD14, CD36, and CD11b extracellular receptor proteins. Several approaches used in this study indicate that HSP‐induced cytokine secretion is largely independent of any contaminating LPS in the samples.

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Blocking peptides and molecular mimicry as treatment for kidney disease

Cited by 6 publications

References 75 publications

Peptide Blocking Self-Polymerization of Extracellular Calcium-Sensing Receptor Attenuates Hypoxia-Induced Pulmonary Hypertension

Peptide Blocking Self-Polymerization of Extracellular Calcium-Sensing Receptor Attenuates Hypoxia-Induced Pulmonary Hypertension

Bidirectional Dysregulation of AMPA Receptor-Mediated Synaptic Transmission and Plasticity in Brain Disorders

Exogenous heat shock proteins HSPA1A and HSPB1 regulate TNF‐α, IL‐1β and IL‐10 secretion from monocytic cells

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