Design of Potent and Proteolytically Stable Oxyntomodulin Analogs

Muppidi, Avinash; Zou, Huafei; Yang, Pengyu; Chao, Elizabeth; Sherwood, Lance; Núñez, Vanessa; Woods, Ashley K.; Schultz, Peter G.; Lin, Qing; Shen, Weijun

doi:10.1021/acschembio.5b00787

Cited by 39 publications

(37 citation statements)

References 37 publications

(73 reference statements)

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“…administration and a half-life of 2-3 h after s.c. administration in humans (34). Previously, we showed that one could staple two turns of the alpha-helix of oxyntomodulin with a biaryl cross-linker to improve potency and half-life (35). We have further developed this approach with a novel, tunable staple engineered with a serum protein binding motif to significantly improve the potency and serum half-life of the stapled peptide.…”

Section: Resultsmentioning

confidence: 99%

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

Yang

Zou

Chao

et al. 2016

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

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Antidiabetic treatments aiming to reduce body weight are currently gaining increased interest. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist administered twice daily via s.c. injection, improves glycemic control, often with associated weight reduction. To further improve the therapeutic efficacy of exendin-4, we have developed a novel peptide engineering strategy that incorporates a serum protein binding motif onto a covalent side-chain staple and applied to the peptide to enhance its helicity and, as a consequence, its potency and serum half-life. We demonstrated that one of the resulting peptides, E6, has significantly improved half-life and glucose tolerance in an oral glucose tolerance test in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism, and also reduced hepatic steatosis in diet-induced obese mice. Moreover, the high potency of E6 allowed us to administer this peptide using a dissolvable microstructure-based transdermal delivery system. Pharmacokinetic and pharmacodynamic studies in guinea pigs showed that a single 5-min application of a microstructure system containing E6 significantly improved glucose tolerance for 96 h. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones.GLP-1 receptor agonist | helix stabilization | half-life extension | microstructure array | lipidated cross-linker B -family G protein-coupled receptors (GPCRs) include receptors for peptide hormones such as glucagon, glucagonlike peptides 1 and 2 (GLP-1 and -2), parathyroid hormone (PTH), and corticotropin-releasing factor. Attempts to generate smallmolecule modulators of these receptors have had limited success, whereas peptide ligands have been proven as effective therapeutic agents, as exemplified by exenatide (aka exendin-4 or Ex-4), a GLP-1 receptor agonist for diabetes, and teriparatide, a PTH1 receptor agonist for osteoporosis (1). However, peptide-based drugs generally suffer from short half-lives due to proteolytic degradation and fast renal clearance, rendering higher doses and frequent injections necessary, which negatively affects patient compliance (2). To improve their pharmacological properties, peptides have been chemically modified by conformational restriction (3-13) to increase potency and reduce proteolysis, and also by lipidation (14-16), polymer conjugation (17-23), and protein fusion (24-26) to decrease renal clearance. Although these latter conjugates can have enhanced circulatory half-lives, they often suffer from reduced potency and, as a result, require injection of relatively large quantities of the modified peptides.GLP-1 receptor agonists (GLP-1RAs) represent a unique approach to the treatment of diabetes, with benefits beyond glucose control, including favorable effects on body weight, blood pressure, cholesterol levels, and beta-cell function (27). Two short-acting (exenatide and liraglutide; on...

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Section: Resultsmentioning

confidence: 99%

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

Yang

Zou

Chao

et al. 2016

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

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“…Alkene RCM on peptides was first reported b9y Blackwell and Grubbs, who reported solution‐phase metathesis and ensuing hydrogenation of i to i +4 systems to generate paraffinic staples . Stapling between the i to i +7 positions was also pursued, such as in the stabilization of oxyntomodulin analogues through biaryl crosslinking of two cysteine residues . By introducing azide‐ and alkyne‐terminated amino acids into the sequence, copper‐catalyzed azide–alkyne cycloaddition (CuAAC) has also been successfully adapted to peptide stapling by a number of research groups (Figure ) …”

Section: Figurementioning

confidence: 99%

Rigid Peptide Macrocycles from On‐Resin Glaser Stapling

et al. 2018

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Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between β-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 α-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles.

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“…Thus, it is necessary to produce long-lasting analogues for clinical use. As discussed above, the substitution of the naturally occurring -Ala at position 2 in incretin results in DPP-IV resistance, and the C-terminal PEGylation and fatty acid derivatization of incretins results in reduced renal clearance by which several long-acting OXM analogues have been successfully developed (Muppidi et al, 2016). Indeed, a recent study of six novel OXM analogues has revealed that OXM-based peptides with specific N-terminal position 2 modifications are stable and show particular promise for the treatment of diabetes (Lynch et al, 2014).…”

Section: Oxm and T2dmmentioning

confidence: 99%

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Hölscher

2016

Reviews in the Neurosciences

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AbstractIncretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.

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Design of Potent and Proteolytically Stable Oxyntomodulin Analogs

Cited by 39 publications

References 37 publications

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

Rigid Peptide Macrocycles from On‐Resin Glaser Stapling

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

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