Bifunctional PEGylated Exenatide-AmylinomimeticHybridsto Treat Metabolic Disorders: An Example of Long-Acting Dual HormonalTherapeutics.

Peptide hybrids (phybrids) comprisingcovalently linked peptidehormones can leverage independent biological pathways for additiveor synergistic metabolic benefits. PEGylation of biologics offersenhanced stability, duration, and reduced immunogenicity. These twomodalities can be combined to produce long-acting therapeutics withdual pharmacology and enhanced efficacy. Compound 10iscomposed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic,davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayeddose-dependent and prolonged efficacy for glucose control and bodyweight reduction in rodents with superior in vitroand in vivoactivities compared to those of a side-chainPEGylated phybrid 6. In diet-induced obese (DIO) rats,the weight-loss efficacy of 10was similar to that ofa combination of PEG-parents 3and 4. Asingle dose of 10elicited sustained body weight reductionin DIO rats for at least 21 days. Compound 10’sterminal half-life of ∼27 h should translate favorably to weeklydosing in humans. [ABSTRACT FROM AUTHOR]