Peptide-based drug design is gaining traction in oncology. This overview covers peptide drugs for cancer immunotherapy targeting PD-L1 and macrophages, apoptosis-inducing peptides such as RA-V and KLA conjugates, peptides for tumor enrichment like ALOS-4 and NT4, and peptide drug conjugates with…
Peptide drug design has drawn considerable interest as bioinformatics knowledge of peptides and proteins expands. Earlier peptide drugs faced limitations such as low selectivity and rapid degradation in biological systems. In recent years, however, new peptide-based therapies have emerged with strong anti-tumor activity, and many are being developed into promising anti-cancer drugs.
The immune system offers a key target for peptide drugs. PD-L1 is highly expressed on many cancer cells. When it binds to PD-1 on activated T cells, the cancer cells escape immune attack. Blocking the PD-1/PD-L1 interaction is therefore a potential immunotherapy strategy. Studies have demonstrated that a hydrophilic D-type peptide called D-PPA has no direct cytotoxicity. By blocking PD-1/PD-L1 binding, D-PPA inhibited tumor growth in CT26 tumor-bearing mice and prolonged their survival.
Macrophages are immune cells with roles in innate and adaptive immunity. The CSF-1/CSF-1R signaling pathway is important for macrophage survival and differentiation. In a recent study, a peptide designated M2pep Cys-YeqDPwGVKWWY was modified to increase specificity for M2 tumor-associated macrophages TAMs . Co-encapsulation of CSF-1R siRNA with this M2pep construct successfully targeted M2 TAMs, causing them to remodel into the M1 phenotype and boosting anti-tumor immune responses.
Certain peptides can directly trigger apoptosis in cancer cells. The anticancer peptide RA-V, also known as deoxybouvardin, induces mitochondrial apoptosis in tumor cells, leading to loss of mitochondrial function. Another pentapeptide, Dolastatin 10, promotes apoptosis by up-regulating cytochrome C and Bax.
The pro-apoptotic peptide KLA sequence KLAKLAKLAK disrupts the mitochondrial membrane to induce programmed cell death. Bioconjugates containing KLA are being explored for various anticancer applications. For instance, KLA can be linked to the tumor-homing peptide IRGD CRGDKGPDC to improve penetration into tumor tissues and cells. A recombinant KLA-IRGd conjugate showed potent anti-tumor effects, high tumor selectivity, and low systemic toxicity in mouse models. Such studies may lead to novel peptide-drug conjugates PDCs .
Another KLA-based approach uses penetratin, a cell-penetrating peptide. Because KLA has low cellular permeability, penetratin was conjugated to KLA via disulfide bonds. The resulting penetratin-KLA conjugate exhibited high cellular permeability and cytotoxicity, even at low concentrations, while having little effect on normal cell mitochondria. This highlights its potential as a new peptide conjugate therapy.
Several strategies use peptides to selectively target tumors. The S-S-bridged cyclic peptide ALOS-4 is specific for integrin AVβ3, which is highly expressed in human metastatic melanoma. In one study, ALOS-4 was coupled to the topoisomerase I inhibitor camptothecin. The conjugate demonstrated potent anti-tumor activity against human metastatic melanoma cells but low toxicity to normal cells.
In another example, researchers conjugated the four-branched peptide NT4 to paclitaxel PTX . NT4 selectively binds to tumor membrane glycosaminoglycans sulfate. When combined with paclitaxel, NT4 showed high selectivity for cancer cells and more potent anti-tumor activity than paclitaxel alone.
Albumin-binding peptides have also been investigated for tumor targeting. In vitro experiments showed that the bioconjugate DICLPRWGCLW forms a stable albumin complex that can target tumors. In SCC7 tumor-bearing mice, this complex exhibited high tumor targeting and a significantly increased half-life. Because albumin uptake correlates positively with tumor growth, albumin binding may become a novel therapeutic strategy for targeting tumor tissues.
Under the concept of drug conjugates, peptides can be combined with cytotoxic drugs or other therapeutic agents to create peptide-based therapies. Several studies have shown that cytotoxic drugs can be attached to peptides with additional functions. For example, platinum-based cisplatin chemotherapy remains one of the most widely used cancer treatments. However, because of cisplatin resistance, long-term use of cisplatin in patients reduces its efficacy. This limitation continues to drive research into alternative peptide-drug conjugates.
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