2 research outputs found
Bifunctional PEGylated Exenatide-Amylinomimetic Hybrids to Treat Metabolic Disorders: An Example of Long-Acting Dual Hormonal Therapeutics
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 <b>10</b> 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 <i>in vitro</i> and <i>in vivo</i> activities compared to those of a side-chain
PEGylated phybrid <b>6</b>. In diet-induced obese (DIO) rats,
the weight-loss efficacy of <b>10</b> was similar to that of
a combination of PEG-parents <b>3</b> and <b>4</b>. A
single dose of <b>10</b> elicited sustained body weight reduction
in DIO rats for at least 21 days. Compound <b>10</b>’s
terminal half-life of ∼27 h should translate favorably to weekly
dosing in humans