Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Abstract

Building 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/smallmolecule 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. ■ SIGNIFICANCE• Juxtaposition of peptide−drug conjugates and antibody−drug conjugates with a focus on challenges that can be overcome with peptide−drug conjugate strategies. • Considerations for the design and optimization of peptide−drug conjugates. • Analysis of several peptide−drug conjugate series that demonstrate effectiveness toward drug-resistant infections and complex disease states.

Celebrating the 60th Anniversary of the MIKIW Meeting-in-Miniature: Virtual Special Issue

“…Finally, in this Virtual Special Issue, you will find several diverse sets of Viewpoints and Perspectives, including a comprehensive analysis of FDA-approved drugs for cancer chemotherapy that function through DNA adducts; a Perspective on the development of peptide–drug conjugates as emerging therapeutic modalities; a Perspective highlighting Gram-negative bacteria drug design, the multifaceted approaches being employed, and current gaps in knowledge for compound development; a personal perspective from one of the early student trainees of the MIKIW meeting; and a Viewpoint from recent MIKIW Keynote speaker, Nick Meanwell, describing opportunities for exploiting the concept of target vulnerability through optimizing drug–target interactions with high levels of cooperativity …”

Recent Advances in Targeted Cancer Therapy: Are PDCs the Next Generation of ADCs?

“…On the other hand, antibodies are typically larger and have more complex structures, which generally confer greater stability and slower degradation in vivo . Peptides are generally considered safe because they have low immunogenicity and produce nontoxic metabolites. The relatively short half-life of PDCs enables quicker metabolism within the body, thereby reducing the potential for toxic side effects, while antibodies are immunogenic and can generate immune responses. , Peptides can be used for a wider range of targets, which is conducive to expanding the application of PDCs, while antibodies are more specific and have a stronger affinity for the target The structure of PDCs is more flexible and easier to modify, enabling them to accommodate a larger quantity of toxic molecules; in other words, they exhibit a higher drug–peptide ratio (DPR), which is distinct from that of DAR .…”

“…Peptides can be used for a wider range of targets, which is conducive to expanding the application of PDCs, while antibodies are more specific and have a stronger affinity for the target …”

“…Similar to the innovations in ADCs, researchers have not limited the range of treatments available for PDCs. Trevor et al provided examples of antibacterial PDCs, antiviral PDCs, anti-inflammatory PDCs and CNS-targeted PDCs . Modifications of the linker and payload of ADCs could also be applied to PDCs.…”