RESUMO
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.