Peptide Derivatives of Erythropoietin in the Treatment of Neuroinflammation and Neurodegeneration

Ercan, İlkcan; Tüfekci, Kemal Uğur; Karaca, Ezgi; Genç, Şermin; Genç, Kürşad

doi:10.1016/bs.apcsb.2018.01.007

Cited by 10 publications

(13 citation statements)

References 163 publications

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“…This denotes nonspecific binding behavior at the surface of the cell, similar to FITC (data not shown). Furthermore, to study the hepatotoxicity effects of the drug, 39 Arg9‐NP1 and Arg9 were treated with HepG2 cells (Figure S8). At inhibitor concentrations of IC 75 , IC 50 , and IC 25 , both Arg9‐NP1 and Arg9 showed less toxicity at higher concentrations, comparable to erlotinib, which showed more than 50% toxicity at these concentrations.…”

Section: Resultsmentioning

confidence: 99%

A novel cyclic NP1 reveals obstruction of EGFR kinase activity and attenuation of EGFR‐driven cell lines

Jiwacharoenchai

Tabtimmai

Kiriwan

et al. 2021

J of Cellular Biochemistry

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Aberrations of the epidermal growth factor receptor (EGFR), for example, mutations and overexpression, play pivotal roles in various cellular functions, such as proliferation, migration, and cell differentiation. Approved small molecule‐based inhibitors, including gefitinib and erlotinib, are used clinically to target the tyrosine kinase domain of EGFR (TK‐EGFR). However, the severity of the side effects, off‐target effects, and drug resistance is a concern. Cyclic peptides are a well‐known peptide format with high stability and are promising molecules for drug development. Herein, the Ph.D.™‐C7C phage display library was used to screen cyclic peptides against TK‐EGFR. Biopanning, both with and without propagation methods, was performed to assess the highest capacity peptides using the enzymatic activity of TK‐EGFR. Interestingly, NP1, a peptide selected during biopanning without propagation demonstrated an inhibitory effect against TK‐EGFR at IC50 within the nanomolar range; this effect was better than that of P1 obtained using biopanning with propagation. Moreover, NP1 elicited EGFR with an affinity binding (KD) value of 18.40 ± 5.50 µM by surface plasmon resonance (SPR). Introducing cell‐penetrating peptides or Arginine‐9 (Arg9) at the N‐terminus of NP1 thus improves cell‐penetrability and can lead to the inhibition of EGFR‐driven cancer cell lines; however, it exhibits no hepatotoxicity. Furthermore, NP1 caused a decrease in phosphorylated EGFR after activation within cells. A docking model shows that NP1 interacted primarily with TK‐EGFR via hydrogen bonding. Together, this suggests that NP1 is a novel EGFR peptide inhibitor candidate with specificity and selectivity toward TK‐EGFR, and may be applied to targeted therapy.

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Section: Resultsmentioning

confidence: 99%

A novel cyclic NP1 reveals obstruction of EGFR kinase activity and attenuation of EGFR‐driven cell lines

Jiwacharoenchai

Tabtimmai

Kiriwan

et al. 2021

J of Cellular Biochemistry

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“…To overcome the unwanted erythropoietic stimulation and maintain the cytoprotective effects, non-erythropoietic analogs have been synthetized via chemical modifications of EPO. These analogs include carbamylated EPO (CEPO), glutaraldehyde EPO –obtained by chemical modification of the lysine residues-, Neuro-EPO – an analog with low sialic acid content-, EPOL – a variant with low glycosylation- and neuropoietin – a less acidic EPO isoform (Leist et al, 2004; Mattio et al, 2011; Rodriguez Cruz et al, 2017; Castillo et al, 2018; Ercan et al, 2018). Recently, smaller EPO-mimetic have also been developed.…”

Section: Erythropoietin As Therapeutic Compoundmentioning

confidence: 99%

“…For a recent review on the topic see (Ercan et al, 2018). EPO mimetics consist either of short peptides homologous to specific sequences of EPO molecule or of non-homologous compounds, peptidic or non-peptidic, which are able to bind EPO receptor and induce its activation (Ercan et al, 2018). Further advances have been made also concerning administration route.…”

Section: Erythropoietin As Therapeutic Compoundmentioning

confidence: 99%

Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

Boesch

Indelicato

2019

Front. Neurosci.

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Friedreich ataxia (FRDA) is a rare neurological disorder due to deficiency of the mitochondrial protein frataxin. Frataxin deficiency results in impaired mitochondrial function and iron deposition in affected tissues. Erythropoietin (EPO) is a cytokine which was mostly known as a key regulator of erythropoiesis until cumulative evidence showed additional neurotrophic and neuroprotective properties. These features offered the rationale for advancement of EPO in clinical trials in different neurological disorders in the past years, including FRDA. Several mechanisms of action of EPO may be beneficial in FRDA. First of all, EPO exposure results in frataxin upregulation in vitro and in vivo . By promoting erythropoiesis, EPO influences iron metabolism and induces shifts in iron pool which may ameliorate conditions of free iron excess and iron accumulation. Furthermore, EPO signaling is crucial for mitochondrial gene activation and mitochondrial biogenesis. Up to date nine clinical trials investigated the effects of EPO and derivatives in FRDA. The majority of these studies had a proof-of-concept design. Considering the natural history of FRDA, all of them were too short in duration and not powered for clinical changes. However, these studies addressed significant issues in the treatment with EPO, such as (1) the challenge of the dose finding, (2) stability of frataxin up-regulation, (3) continuous versus intermittent stimulation with EPO/regimen, or (4) tissue changes after EPO exposure in humans in vivo (muscle biopsy, brain imaging). Despite several clinical trials in the past, no treatment is available for the treatment of FRDA. Current lines of research focus on gene therapy, frataxin replacement strategies and on regulation of key metabolic checkpoints such as NrF2. Due to potential crosstalk with all these mechanisms, interventions on the EPO pathway still represent a valuable research field. The recent development of small EPO mimetics which maintain cytoprotective properties without erythropoietic action may open a new era in EPO research for the treatment of FRDA.

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“…Recently, a number of peptides derived from helices A, B, or C or the AB loop have been evaluated by independent investigators and shown to provide potent anti‐inflammation and tissue protection (reviewed in Ercan et al . 18 ). For example, we have prepared a number of peptides derived from structure of helix B of EPO which interact with the innate repair receptor and not the homodimer of EPO‐R, providing significant benefit.…”

Section: Introductionmentioning

confidence: 99%

The erythropoietin‐derived peptide ARA 284 reduces tissue wasting and improves survival in a rat model of cancer cachexia

Palus

Elkina

Braun

et al. 2022

J cachexia sarcopenia muscle

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Background Cancer cachexia (CC) is a severe complication during the last stages of the disease, which is characterized by the substantial loss of muscle and fat mass. Currently, there is no effective treatment of CC. Erythropoietin plays tissue‐protective role in different tissues. Based on the structure of erythropoietin, small non‐erythropoietic peptides were synthesized, which activate tissue‐protective signalling pathways. Methods Here, we investigated the influence of the tissue‐protective peptide ARA 284 on CC in rats using the Yoshida hepatoma model. Results Treatment with ARA 284 (1.7 μg/kg/day) counteracted the loss of body weight (12.46 ± 4.82% ARA 284 vs. 26.85 ± 0.88% placebo, P < 0.01), fat mass (P < 0.01), and lean mass (P < 0.01). It improved spontaneous activity of ARA 284‐treated animals. Further, gastrocnemius mass was increased (13.2% ARA 284 vs. placebo, P < 0.01) in association with induced p‐Akt (P < 0.01) and decreased in p‐p38 MAPK, GSK‐3β, and myostatin (all P < 0.01), suggesting an induction of anabolic pathways. At the same time, we observed the significant increase in the survival of animals by high‐dose ARA 284 treatment (hazard ratio: 0.46, 95% confidence interval: 0.23–0.94, P = 0.0325). Conclusions Taken together these results suggest that ARA 284 can be considered beneficial in experimental CC and it remains to be seen, if it can have similar beneficial effects in CC patient.

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Peptide Derivatives of Erythropoietin in the Treatment of Neuroinflammation and Neurodegeneration

Cited by 10 publications

References 163 publications

A novel cyclic NP1 reveals obstruction of EGFR kinase activity and attenuation of EGFR‐driven cell lines

A novel cyclic NP1 reveals obstruction of EGFR kinase activity and attenuation of EGFR‐driven cell lines

Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

The erythropoietin‐derived peptide ARA 284 reduces tissue wasting and improves survival in a rat model of cancer cachexia

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