Development of long-acting ciliary neurotrophic factor by site-specific conjugation with different-sized polyethylene glycols and transferrin

Zhang, Chun; Yu, Rong Hua; Li, Zenglan; Feng, Chao; Qi, Wang; Liu, Yongdong; Su, Zhiguo

doi:10.1016/j.ijpharm.2017.06.074

Cited by 5 publications

(7 citation statements)

References 38 publications

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“…This discrepancy likely results from the different route of DH-CNTF administration, with the IP route having higher bioavailability and/or more sustained release. In support of this hypothesis, twice weekly SC administration of wt CNTF at 1 mg/kg in another study [ 19 ] was unable to induce weight loss.…”

Section: Resultsmentioning

confidence: 84%

“…Differently, previous attempts of site-specific attachment of different-sized PEG-maleimide or transferrin residue to wild-type CNTF indicated losses of activity in a survival assay of about 50–60% [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

“…The main difference between the two samples lies in the peak eluted at 8.47 min (calcd. [M] 649.2854 Da, found [M+H] + 650.2908) that corresponds to the fragment F3 [ 15 – 19 ] containing Cys17. Since this peak was only present in DH-CNTF peptide profile and was detected with low intensity in the digested mixture of PEG-DH-CNTF, we may infer that the site of modification with PEG is the Cys17 residue.…”

Section: Resultsmentioning

confidence: 99%

“…Previous PEG20K modifications and transferrin (Tf) coupling based on the natural free thiol of Cys17 residue of the wild-type CNTF molecule, have been reported [ 19 ]. Both conjugates led to weight-loss in mice, with PEG20k-CNTF being more potent than Tf-PEG5k-CNTF.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of PEGylated ciliary neurotrophic factor superagonist variant in diet-induced obesity mice

et al. 2022

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Ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine able to induce appetite reduction, weight loss and antidiabetic effects. However, its susceptibility to neutralizing anti-CNTF antibodies in patients hampered its use for treatment of human obesity and diabetes. In addition, CNTF has a very short plasma half-life, which limits its use as a therapeutic agent. Solutions, directed to prolong its in vivo effects, vary from the implantation of encapsulated secreting cells to identification of more active variants or chemical modification of the protein itself. PEGylation is a widely used modification for shielding proteins from circulating antibodies and for increasing their plasma half-life. Here, we have selected DH-CNTF, a CNTF variant which has a 40-fold higher affinity for the CNTF receptor α accompanied by an increased activity in cellular assays. The PEGylated DH-CNTF retained the biological activity of native protein in vitro and showed a significant improvement of pharmacokinetic parameters. In an acute model of glucose tolerance, the PEG-DH-CNTF was able to reduce the glycemia in diet-induced obese animals, with a performance equaled by a 10-fold higher dose of DH-CNTF. In addition, the PEGylated DH-CNTF analog demonstrated a more potent weight loss effect than the unmodified protein, opening to the use of CNTF as weight reducing agent with treatment regimens that can better meet patient compliance thanks to reduced dosing schedules.

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Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of PEGylated ciliary neurotrophic factor superagonist variant in diet-induced obesity mice

et al. 2022

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“…PEG, owing to its low immunogenicity, high hydrophilicity, and biocompatibility, is an important polymer that is widely applied in protein/peptide delivery for preventing enzyme degradation, decreasing protein immunogenicity, and prolonging half-life via conjugating to protein/peptide therapeutics such as PEGylated tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or PEGylated ciliary neurotrophic factor (CNTF). , For now, 15 kinds of PEGylation protein therapeutics such as Adagen, JIVI, etc . with protein molecular weights ranging from 5,000 to 60,000 were approved by the FDA. − But the circulation time of the PEGylated protein still does not meet the needs for long-term treatment of chronic diseases such as diabetes and cerebral degenerative diseases.…”

Section: Polymer-based Systemsmentioning

confidence: 99%

Sustained Release Systems for Delivery of Therapeutic Peptide/Protein

et al. 2021

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Peptide/protein therapeutics have been significantly applied in the clinical treatment of various diseases such as cancer, diabetes, etc. owing to their high biocompatibility, specificity, and therapeutic efficacy. However, due to their immunogenicity, instability stemming from its complex tertiary and quaternary structure, vulnerability to enzyme degradation, and rapid renal clearance, the clinical application of protein/peptide therapeutics is significantly confined. Though nanotechnology has been demonstrated to prevent enzyme degradation of the protein therapeutics and thus enhance the half-life, issues such as initial burst release and uncontrollable release kinetics are still unsolved. Moreover, the traditional administration method results in poor patient compliance, limiting the clinical application of protein/peptide therapeutics. Exploiting the sustained-release formulations for more controllable delivery of protein/peptide therapeutics to decrease the frequency of injection and enhance patient compliance is thus greatly meaningful. In this review, we comprehensively summarize the substantial advancements of protein/peptide sustainedrelease systems in the past decades. In addition, the advantages and disadvantages of all these sustained-release systems in clinical application together with their future challenges are also discussed in this review.

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