Long-Acting, Longer-Acting, and Ultralong-Acting Antiobesity Peptides

This perspective describes the current status and future prospects of developing long- to ultralong-acting anti-obesity peptides. First, we discuss the current status of lipidation, PEGylation, and Fc fusion technologies to obtain long-acting peptides administered once weekly, and we critique their proposed use for longer dosing intervals. Next, we describe the approach and current results of using macromolecular peptide prodrugs with preprogrammed releasable linkers to achieve longer-acting peptides that can be administered weekly or monthly. Finally, we posit novel modifications of the latter technology that could provide ultralong half-lives of over one month by advantageously exploiting the clearance rates of released peptides. As examples, we posit that prodrugs of low-clearance GLP-1 agonists derived from peptides already modified by lipidation, PEGylation, and Fc fusion could produce ultralong-acting agonists with dosing intervals reaching 3 to even 6 months.