Recent Advances in Augmenting the Therapeutic Efficacy of Peptide-Drug Conjugates

Abstract

There is an urgent need for the development of safe and effective modalities for the treatment of diseases owing to drug resistance, undesired side effects, and poor clinical outcomes. Combining cell-targeting and efficient cell-killing properties, peptide-drug conjugates (PDCs) have demonstrated superior efficacy compared with peptides and payloads alone. However, innovative molecular designs of PDCs are essential for further improving targeting precision, protease resistance and stability, cell permeability, and overall treatment efficacy. Several strategies have been developed to address these challenges, such as multivalency approaches, bispecific targeting, and long-acting PDCs. Other novel strategies, including overcoming biological barriers, conjugating novel functional payloads, and targeting macropinocytosis, have also shown promise. This perspective compiles the most recent strategies for enhancing PDC treatment efficacy, highlights key advancements in PDC, and provides insights on future directions for the development of novel PDCs.

Figure 1

Schematic structure of a peptide–drug conjugate (PDC) and chemical structures of FDA-approved PDCs. (1) Lutathera features a cell-targeting peptide (CTP) derived from the tyrosine-containing somatostatin analogue Tyr3-octreotate (TATE), an amide bond linker, and a payload comprising the macrocyclic chelating agent tetraazacyclododecane-tetraacetic acid (DOTA) bound to the beta-emitting radionuclide lutetium-177 (¹⁷⁷Lu). (2) Pluvicto contains a CTP with the PSMA-binding motif Glu–NH–CO–NH–Lys, a linker incorporating 2-naphthyl-l-alanine and tranexamic acid, and the same payload as the Lutathera. (3) The CTP is shown in blue, the payload in orange, and the linker in black.

Figure 2

Mechanism of action of PDCs. PDCs can enter cells via endocytosis mediated by CTPs or small-molecule payloads. Alternatively, they may cross the membrane through CPPs. The low acidity and high enzyme concentrations in endosomes or lysosomes facilitate the release of payloads into the cytoplasm, nucleus, or other organelles to exert their functions.

Figure 3

Representative peptides utilized in PDCs. The amino acid sequences of some typical CTPs are shown in the left box, where the amino acid in red color is a non-natural amino acid. The boxes on the right are examples of SRP, CPP, and SAP, respectively.

Figure 4

Chemical structures of different linkers in PDCs. The peptide is shown in rainbow color and the linker in black.

Figure 5

Schematic representation of the most common conjugate reactions used in PDCs. The peptide moieties are highlighted in rainbow color.

Figure 6

Overview of the current challenges and optimizations of PDCs.

Figure 7

Chemical structures of small molecular albumin-binding moieties.

Figure 8

Chemical structures of albumin-binding fatty acids (in black color) used in long-acting peptide drugs and PDCs.

Figure 9

Chemical structures of representative payloads of PDCs. The payload and linker conjugating functional groups are highlighted in red.