Peptide Conjugates with Small Molecules Designed to Enhance Efficacy and Safety

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.

Protease‐activated prodrugs: strategies, challenges, and future directions

“…One of the main drawbacks of PDCs is their short half‐life in blood, due to their relatively small size, and these conjugates are susceptible to clearance. However, their rapid tissue distribution compensates for this unfavorable characteristic . To date, multiple cell‐penetrating and tumor‐homing peptides have been developed, and some of them have already reached clinical trials .…”

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos

“…In fact, these are equipped with desired physicochemical features to involuntarily aggregate as well as accumulate at target sites (Su et al, 2015). Since peptides can be manufactured effortlessly in large quantities and need simple purification, their range of selection of peptide sequences as per the requisite physicochemical properties like stability, solubility, overall charge and availability of the characteristic groups for the conjugation with the therapeutic payload, these are considered as sought-after prodrugs (He et al, 2019).…”

Engineering small molecule nanodrugs to overcome barriers for cancer therapy

“…Among these drug derivatives, drug oligopeptide conjugates are the most widely studied recently. Several review papers 82,83 have already summarized the design principles of peptide-drug conjugate, including selecting the cytotoxic agents, linker technology, and oligopeptides. Moreover, both water-soluble drug-peptide conjugates and self-assembling drug-peptide conjugates for targeted drug delivery and cancer chemotherapy have been reviewed in 2016.…”