Abstract
Opioids are a powerful class of medicines due to their ability to alleviate acute pain. However, the use of prescription opioids has led to an epidemic in the United States. Many efforts to combat this are ongoing, including the preparation of misuse deterrent opioid formulations, some of which can be subverted using common household chemicals. Herein, the development of an oxycodone-containing peptide prodrug is reported that contains three covalent misuse deterrent protective layers. This prodrug is resistant to degradation in the presence of acidic and basic pH conditions, common household chemicals, and enzyme supplements. After optimization of the peptide sequence, the lead prodrug is composed of a branched lysine residue coupled to a tert-butyl-protected tyrosine that is not naturally recognized by digestive enzymes. There is a necessary sequence of protecting group removal and then subsequent enzymatic peptide cleavages that trigger cyclization of a self-immolative linker to release the opioid agonist, oxycodone. The prodrug has analgesic properties in vivo in mice only after oral administration and not by intraperitoneal injection, which suggests that this prodrug may have misuse deterrent properties. The specificity for dual-enzyme release and the resulting in vivo studies warrant further examination of this prodrug scaffold for its potential as a misuse deterrent alternative to treat acute pain.