Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers

Chae, Su Young; Chun, Young Goo; Lee, Seulki; Jin, Cheng‐Hao; Lee, Eun Seong; Lee, Kang Choon; Youn, Yu Seok

doi:10.1002/jps.21532

Cited by 33 publications

(23 citation statements)

References 31 publications

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“…The larger EC 50 of the GLP-1 fusions compared to GLP1 is to be expected because macromolecular conjugates of GLP-1, such as an ELP or ZIPP, can sterically hinder the interaction between GLP-1 and its receptor and reduce their potency. This finding is also consistent with the 30-500 lower potency of PEGylated GLP1 relative to the unmodified peptide [72].…”

Section: In Vitro Activity Of Glp1 Fusionssupporting

confidence: 84%

Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery

et al. 2019

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The clinical utility of many peptide and protein drugs is limited by their short in-vivo half-life. To address this limitation, we report a new class of polypeptide-based materials that have a long plasma circulation time. The design of these polypeptides is motivated by the hypothesis that incorporating a zwitterionic sequence, within an intrinsically disordered polypeptide motif, would impart "stealth" behavior to the polypeptide and increase its plasma residence time, a behavior akin to that of synthetic stealth polymers. We designed these zwitterionic polypeptides (ZIPPs) with a repetitive (VPX 1 X 2 G) n motif, where X 1 and X 2 are cationic and anionic amino acids, respectively, and n is the number of repeats. To test this hypothesis, we synthesized a set of ZIPPs with different pairs of cationic and anionic residues with varied chain length. We show that a combination of lysine and glutamic acid in the ZIPP confer superior pharmacokinetics, for both intravenous and subcutaneous administration, compared to uncharged control polypeptides.Finally, to demonstrate their clinical utility, we fused the best performing ZIPP sequence to glucagon-like peptide-1 (GLP1), a peptide drug used for treatment of type-2 diabetes and show Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supporting InformationSupporting Information is attached. The raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

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Section: In Vitro Activity Of Glp1 Fusionssupporting

confidence: 84%

Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery

et al. 2019

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“…Furthermore, activity analysis of a trx fusion protein, trx-ELP(10FA), indicate at most a 50% activity loss (in the absence or presence of HSA), as compared with free trx. This compares favorably with other carriers reported to cause an ∼30to 500-fold reduction in the activity of other peptides (38)(39)(40)(41)(42). Although, as is true for any carrier, the effect of ELP fusion and FA conjugation on activity is expected to vary for each individual peptide, protein, or molecule, our proposed fusion partner is highly tunable, in ELP size, sequence, and FA number and position, which should enable future optimization of both pharmacokinetics and bioactivity of each drug candidate.…”

Section: Discussionsupporting

confidence: 79%

Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids

Vanderschuren

Arranz‐Gibert

Khang

et al. 2022

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

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The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these challenges, we use a genomically recoded organism to produce genetically encoded elastin-like polypeptide–protein fusions containing multiple instances of para-azidophenylalanine (pAzF). Precise lipidation of these pAzF residues generated a set of sequence-defined synthetic biopolymers with programmable binding affinity to albumin without ablating the activity of model fusion proteins, and with tunable blood serum half-lives spanning 5 to 94% of albumin’s half-life in a mouse model. Our findings present a proof of concept for the use of genetically encoded bioorthogonal conjugation sites for multisite lipidation to tune protein stability in mouse serum. This work establishes a programmable approach to extend and tune the half-life of protein or peptide therapeutics and a technical foundation to produce functionalized biopolymers endowed with programmable chemical and biophysical properties with broad applications in medicine, materials science, and biotechnology.

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“…This finding was not surprising, given that fusion of GLP1 to albumin results in a 30-fold reduction in bioactivity 36 . This was also better than conjugation of GLP1 to PEG, which reduced receptor affinity by 30- to 500-fold 37 . Although there is a trend towards reduced potency for fusions with lower T t ’s, this trend is not significant and was likely due to their greater propensity to transition and aggregate at the assay temperature (37°C); such aggregation could sterically hinder interaction with the GLP1 receptor.…”

Section: Resultsmentioning

confidence: 98%

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer

et al. 2017

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Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes because of pleiotropic effects, including the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-live owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics leads to 10 days of glycemic control in three different mouse models of diabetes, as well as to the reduction of glycosylated hemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.

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Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers

Cited by 33 publications

References 31 publications

Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery

Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery

Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer

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