Peptide-Drug Conjugates with Different Linkers for Cancer Therapy

Abstract

Drug conjugates are chemotherapeutic or cytotoxic agents covalently linked to targeting ligands such as an antibody or a peptide via a linker. While antibody-drug conjugates (ADCs) are now clinically established for cancer therapy, peptide-drug conjugates (PDCs) are gaining recognition as a new modality for targeted drug delivery with improved efficacy and reduced side effects for cancer treatment. The linker in a drug conjugate plays a key role in the circulation time of the conjugate and release of the drug for full activity at the target site. Herein, we highlight the main linker chemistries utilized in the design of PDCs and discuss representative examples of PDCs with different linker chemistries with the related outcome in cell and animal studies.

Figure 1.

Schematic of a PDC. The chemical structures of different linker chemistries are shown with the plausible method of release of the drug from PDC after cellular uptake or under in vivo conditions.

Figure 2.

PDCs with an ester and/or an amide as linkers. The peptide is shown in red, the linker in blue, and the drug in black. D-amino acids are shown in lower case.

Figure 3.

PDCs with a carbamate linker. D-amino acids are shown in lower case.

Figure 4.

PDCs with a dipeptide or tripeptide linker.

Figure 5.

PDCs with an amide and a succinimidyl thioether as linkers.

Figure 6.

Peptide-drug conjugate with the ring closed succinimidyl thioether and ring-open stable thioether.

Figure 7.

PDCs with an ester and a triazole as linkers.

Figure 8.

Drug conjugates with a hydrazone bond as a linker.

Figure 9.

PDCs with a disulfide as a linker.

Figure 10.

PDCs with an oxime as a linker.

Figure 11.

PDC with triazole linkers.

Figure 12.

Structures of some approved ADCs with different linker chemistries. The antibody is shown in green, the linker in blue, and the drug in black.