Dirk Vetter

Tailor made pharmacokinetics of peptides by transient PEGylation.

Introduction Conjugation to polyethylene glycol (PEGylation) is widely used in order to prolong the pharmacodynamic effect of proteins. For peptides, PEGylation requires extensive engineering to retain sufficient pharmacological activity (receptor affinity, tissue penetration) of the conjugate. Transient PEGylation is based on the release of unmodified peptide from a PEG carrier thus obviating the need for engineering. Peptide liberation proceeds via slow cleavage of a traceless linker under physiological conditions. Linker cleavage should ideally be governed primarily by pH and temperature in order to avoid enzyme dependent intrapatient variability as it is known e.g. for ester prodrugs. Several linkers have been proposed for transient PEGylation so far, mostly depending on enyzmatic activation and with half life times less than 24 h [1]. We developed a family of linker structures that cleave after initial hydrolysis of a carbamate bond (Fig. 1). The first hydrolytic step is rate determining and depends on the structure of the internal trigger and linker scaffold.