Novel Peptide Therapeutic Approaches for Cancer Treatment

Abstract

Peptides are increasingly being developed for use as therapeutics to treat many ailments, including cancer. Therapeutic peptides have the advantages of target specificity and low toxicity. The anticancer effects of a peptide can be the direct result of the peptide binding its intended target, or the peptide may be conjugated to a chemotherapy drug or radionuclide and used to target the agent to cancer cells. Peptides can be targeted to proteins on the cell surface, where the peptide-protein interaction can initiate internalization of the complex, or the peptide can be designed to directly cross the cell membrane. Peptides can induce cell death by numerous mechanisms including membrane disruption and subsequent necrosis, apoptosis, tumor angiogenesis inhibition, immune regulation, disruption of cell signaling pathways, cell cycle regulation, DNA repair pathways, or cell death pathways. Although using peptides as therapeutics has many advantages, peptides have the disadvantage of being easily degraded by proteases once administered and, depending on the mode of administration, often have difficulty being adsorbed into the blood stream. In this review, we discuss strategies recently developed to overcome these obstacles of peptide delivery and bioavailability. In addition, we present many examples of peptides developed to fight cancer.

Keywords: PCNA; covalent-based peptide inhibitors; drug delivery; peptide therapeutic.

Figure 1

Current methods to enhance the half-life of peptide drugs and improve peptide drug delivery include (A) peptide cyclization, (B) manipulation of the amino acid sequence, (C) peptide-loaded nanoparticles, and (D) the conjugation of peptide drugs to natural or synthetic polymers.

Figure 2

Schematic of targeting PCNA-binding proteins, such as FEN1. (A) Structure of the PCNA trimer (orange, blue, and black subunits) complexed to FEN1 (gray) [PDB ID: 1UL1 [97]]. The caPeptide region of PCNA (amino acids 126–133) is shown in green [PDB ID: 6FCM [108]]. (B) R9-caPeptide (labeled in dark green) binds to FEN1 to disrupt interactions with PCNA. The binding site of caPeptide-FEN1 shown in solution is theoretical. Images were made in the software Chimera [109].