Identification of CJC-1131-albumin bioconjugate as a stable and bioactive GLP-1(7–36) analog

Léger, Roger; Thibaudeau, Karen; Robitaille, Martin; Quraishi, Omar; Wyk, Pieter van; Bousquet-Gagnon, Nathalie; Carette, Julie; Castaigne, Jean‐Paul; Bridon, Dominique

doi:10.1016/j.bmcl.2004.06.066

Cited by 57 publications

(37 citation statements)

References 36 publications

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“…Only for some therapeutics, e.g., cytotoxic substances used in cancer therapy, rapid clearance is an advantage (Janssen et al, 2002). In situations where the circulation time of a peptide has to be prolonged peptides can be conjugated with large carrier molecules, e.g., polyvinyl pyrrolidone (Mu et al, 1999), polysaccharides, e.g., dextran (Melton et al, 1987a,b), polysialic acid (Fernandes and Gregoriadis, 2001), albumin (Leger et al, 2003(Leger et al, , 2004Wong et al, 1980), and others. Conjugation with polyethylene glycol (PEG) is state of the art to improve half-life.…”

Section: Introductionmentioning

confidence: 99%

Effect of oriented or random PEGylation on bioactivity of a factor VIII inhibitor blocking peptide

Kopecky

Greinstetter

Pabinger

et al. 2006

Biotechnol. Bioeng.

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Peptides as therapeutic substances are efficient agents in the treatment of several diseases. However, they often have to be chemically modified in order to be suited as therapeutic agent. Conjugation to large carrier molecules is often required. A critical step is the identification of available sites for chemical reaction, without influencing bioactivity. Peptide 238/S1 with the sequence NH(2)-PYWKWQYKYD-COOH previously selected from a combinatorial decapeptide library, has the ability to block inhibitory antibodies against blood clotting factor VIII (FVIII) and therefore, it constitutes a lead for developing a drug to treat patients suffering from development of such antibodies. The aims of this study were (i) to identify sites of the peptide, which are suited for modification without losing bioactivity and (ii) to find out the influence of molecular size of polyethylene glycol (PEG) for bioactivity of the peptide. The contribution of each amino acid residue to biological functionality was investigated by mutational analysis. This method confirmed that the N-terminus is crucial for activity, whereas both lysine residues could be exchanged by other L-amino acids. Using mutational analysis it was possible to identify peptides with higher reactivity compared to the wild type 238/S1. PEGylation experiments demonstrated that conjugation of the peptide to PEG 20,000 resulted in a loss of reactivity, while PEG 5,000 could maintain the bioactivity when conjugated in a site directed manner. The peptide lost its neutralization properties when PEG was coupled to the N-terminus, again indicating that this part of the peptide is important for functionality.

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Section: Introductionmentioning

confidence: 99%

Effect of oriented or random PEGylation on bioactivity of a factor VIII inhibitor blocking peptide

Kopecky

Greinstetter

Pabinger

et al. 2006

Biotechnol. Bioeng.

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“…CYM2053 is as potent anticonvulsant as three last approved drugs and it is also active in limbic seizures (2010). [46,47] . For glutamate, glycine and GABA receptors in the brain, we will see continued development of allosteric modulators of low molecular weight that can penetrate the BBB.…”

Section: Discussionmentioning

confidence: 99%

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

Bartfai

Wang

2013

Acta Pharmacol Sin

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The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABA A receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world's first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.

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“…In addition, long-term studies concerning clear cardiovascular end-points are needed; there exist many GLP-1 effects on the heart that are either receptor dependent or -independent (Ban et Once daily, phase III (Lyxumia) (Gerich et al, 2010). For ZP10, a prolonged-release formulation exists (Thorkildsen et al, 2003) ; structure in Leger et al, 2004); it allows for covalent binding to endogenous serum albumin and is protected against DPP-4 degradation (Guivarch et al, 2004); its half-life is similar to that of circulating albumin, approximately 10 to 15 days (De León et al, 2006;Nauck and Meier, 2005;Sinclair and Drucker, 2005;Christensen and Knop, 2010): no longer in active clinical development CJC-1134 A similar conjugate of albumin as CJC-1131, albeit with exendin-4 (Baggio and Drucker, 2007;Baggio et al, 2008;Christensen and Knop, 2010). It is given once weekly, in phase II; the half-life of albumin is the basis of the half-life of the compound CJC-1134-PC Same molecule as CJC-1134 except that it originates from exendin-4(1-39) instead of GLP-1 (Baggio et al, 2008 ; half-life of 3-6 h; no new data LY2189265 Phase II (Bastyr et al, 2010;Glaesner et al, 2010) PEG-DAPD PEGylated b DAPD (dual acting peptide for diabetes) ϭ GLP-1/glucagon hybrid peptide containing a maleimide-polyethylene glycol polymer (Claus et al, 2007); no new data Semaglutide (NN9535)…”

Section: E General Commentsmentioning

confidence: 99%

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

Verspohl

2012

Pharmacol Rev

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Identification of CJC-1131-albumin bioconjugate as a stable and bioactive GLP-1(7–36) analog

Cited by 57 publications

References 36 publications

Effect of oriented or random PEGylation on bioactivity of a factor VIII inhibitor blocking peptide

Effect of oriented or random PEGylation on bioactivity of a factor VIII inhibitor blocking peptide

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

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