Bifunctional PEGylated exenatide-amylinomimetic hybrids to treat metabolic disorders: an example of long-acting dual hormonal therapeutics.
J Med Chem
; 56(22): 9328-41, 2013 Nov 27.
Article
em En
| MEDLINE
| ID: mdl-24144329
ABSTRACT
Peptide hybrids (phybrids) comprising covalently linked peptide hormones can leverage independent biological pathways for additive or synergistic metabolic benefits. PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produce long-acting therapeutics with dual pharmacology and enhanced efficacy. Compound 10 is composed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic, davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayed dose-dependent and prolonged efficacy for glucose control and body weight reduction in rodents with superior in vitro and in vivo activities compared to those of a side-chain PEGylated phybrid 6. In diet-induced obese (DIO) rats, the weight-loss efficacy of 10 was similar to that of a combination of PEG-parents 3 and 4. A single dose of 10 elicited sustained body weight reduction in DIO rats for at least 21 days. Compound 10's terminal half-life of ~27 h should translate favorably to weekly dosing in humans.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
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Polietilenoglicóis
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Peçonhas
/
Hormônios Peptídicos
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Polipeptídeo Amiloide das Ilhotas Pancreáticas
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Peptidomiméticos
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Doenças Metabólicas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos