Abstract
Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.
Highlights
Peptides represent a powerful class of medicine that currently serves multiple diseases and often constitutes indispensable, life-preserving pharmacology [1,2,3,4]
Similar to drug discovery directed at small molecules, peptide research has evolved in the direction of multimode pharmacology, [20,21,22] where single molecules activate multiple receptors in an additive and occasionally in a synergistic manner to achieve superior efficacy often at reduced dose [1,2,3,4,23,24,25]
We focus on peptide-drug conjugates that promote the integrated benefits of peptides and smaller, non-peptide pharmacophores
Summary
Peptides represent a powerful class of medicine that currently serves multiple diseases and often constitutes indispensable, life-preserving pharmacology [1,2,3,4]. Similar to drug discovery directed at small molecules, peptide research has evolved in the direction of multimode pharmacology, [20,21,22] where single molecules activate multiple receptors in an additive and occasionally in a synergistic manner to achieve superior efficacy often at reduced dose [1,2,3,4,23,24,25] This type of pharmacology is exemplified in purposefully integrated, dual agonism at amylin and calcitonin, GLP-1 and glucagon, or with gastric inhibitory peptide (GIP), and triple agonism at GLP-1, glucagon and GIP in treatment of the metabolic syndrome [26,27,28,29,30,31,32,33,34,35]. We have selectively cited prominent examples of peptide-drug conjugates as representatives of the class to offer our perspective in molecular design, selection of covalent linkers, and other aspects that influence performance
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