Trevor T. Dean, Juliet Jelú-Reyes, A’Lester C. Allen, and Terry W. Moore
Journal of Medicinal Chemistry 2024
DOI: 10.1021/acs.jmedchem.3c01835Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide–drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide–drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody–drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide–drug conjugate design and optimization, such as peptide/small-molecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide–drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms.
