Design and Synthesis of Conformationally Constrained Glucagon-Like Peptide-1 Derivatives with Increased Plasma Stability and Prolonged in Vivo Activity

Miranda, Les P.; Winters, Katherine A.; Gegg, Colin V.; Patel, Ankita; Aral, Jennifer; Long, Jason; Zhang, Jingwen; Diamond, Stephanie; Guido, Mark; Stanislaus, Shanaka; Ma, Mark; Li, Hongyan; Rose, Mark J.; Poppe, Leszek; Véniant, Murielle M.

doi:10.1021/jm701522b

Cited by 73 publications

(88 citation statements)

References 55 publications

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“…We synthesized a library of GLP-1 oligomers wherein a number of variables were systematically explored: (i) number of GLP-1 repeats, (ii) their amino acid composition (14), and (iii) the sequence of the intervening protease cleavage site (21). This library consisted of genes for five different GLP-1 variants, for which oligomers of different lengths were generated, which could then be fused with three different ELPs leading to a potential pool of 75 unique POD designs (Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…First, we chose a GLP-1 analog-[G 8 E 22 ]GLP-that has an alanine (A) to glycine (G) substitution at residue 8 to confer DPPIV resistance and a glycine (G) to glutamic acid (E) substitute at residue 22 (14) to stabilize its α-helical structure. Second, a glycine-alanine (GA) dipeptide was added to the N terminus of each GLP-1 unit to introduce a protease cleavable arginine (R)-glycine (G) pair between successive peptides.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike insulin and other insulin secretagogues (such as sulfonylureas), which act independently of glucose level and therefore increase the risk for hypoglycemia, the insulinotrophic effects of GLP-1 are glucose dependent and vanish when glucose levels drop below 60 mg/dL, preventing potentially lifethreatening hypoglycemia (13). Despite these attractive pharmacological features, native GLP-1 has not been used for treatment of type-2 diabetes because the peptide undergoes rapid deactivation in vivo via N-terminal truncation by dipeptidyl-peptidase IV (DPPIV), leading to an in vivo half-life of less than 2 min (14). To circumvent this problem, DPPIV-resistant GLP-1 analogs have been proposed.…”

mentioning

confidence: 99%

“…To circumvent this problem, DPPIV-resistant GLP-1 analogs have been proposed. However, due to the small size of these GLP-1 analogs, renal clearance still limits the half-life to 4-5 min (14), so that clinically approved formulations of GLP-1 mimetics such as exenatide-a 39 amino acid peptide derived from the Gila monster that has 53% homology to GLP-1-require twice daily injections and cause side-effects such as nausea (15). Hence, a controlled release system of GLP-1 that minimizes injection frequency and provides sustained release of the peptide over time with the potential to minimize the spike in GLP-1 levels that is typical for injection of soluble peptide is highly desirable (16).…”

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confidence: 99%

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Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control

Amiram

Luginbuhl

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide drugs are an exciting class of pharmaceuticals increasingly used for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections and an undesirable "peak-and-valley" pharmacokinetic profile, which can cause undesirable side-effects. Synthetic prolonged release formulations can provide extended release of biologically active native peptide, but their synthetic nature can be an obstacle to production and utilization. Motivated by these limitations, we have developed a new and entirely genetically encoded peptide delivery system-Protease Operated Depots (PODs)-to provide sustained and tunable release of a peptide drug from an injectable s.c. depot. We demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes drug, and a thermally responsive, depot-forming elastin-like-polypeptide that undergoes a thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. We constructed synthetic genes for glucagonlike peptide-1 PODs and demonstrated their high-yield expression in Escherichia coli and facile purification by a nonchromatographic scheme we had previously developed. Remarkably, a single injection of glucagon-like peptide-1 PODs was able to reduce blood glucose levels in mice for up to 5 d, 120 times longer than an injection of the native peptide drug. These findings demonstrate that PODs provide the first genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics.drug delivery | sustained release | peptide polymers W ith more than 40 approved peptide drugs worldwide and over 650 peptides in clinical and preclinical development,

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control

Amiram

Luginbuhl

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Control IgG or 10, 100, or 1,000 nM hGLP-1R antibody was added to cell lines expressing human or mouse GLP-1R, as previously described (15,26). Cells were incubated at 37°C for 20 min before addition of serially diluted GLP-1-(7-36) amide (Bachem Americas) in the presence of 3-isobutyl-1-methylxanthine (Sigma-Aldrich, St. Louis, MO).…”

Section: Experimental Animalsmentioning

confidence: 99%