Target: Cancer. Mission: Search & Destroy.
As we mentioned in the previous issue of our PEPNET newsletter, cancer is a leading cause of death, worldwide. By 2021, it is expected to surpass the current number one cause of death in the United States, cardiovascular diseases. As such, there is an urgent need for research leading to a cure. In Bioorganic & Medicinal Chemistry, Vadim Le Joncour and Pirjo Laakkonen review cancer targeting peptides. Antibodies can be a common cancer-targeting tool, however, they tend to have non-specific binding which can cause toxicity to susceptible tissues, including the bone marrow, liver, and spleen. In addition, their high molecular weight causes them to struggle to properly diffuse. Peptides, on the other hand, tend to be smaller molecules with high specificity, low toxicity, and can be easily modified with the addition of imaging agents or nanocarriers, making them suitable for cancer chemotherapies. The ability to alter peptides at the C-terminus, N-terminus, and side chains, allows for modifications that reduce degradation, improve diffusion, and increase specificity.
Some of the peptide types covered in the review include -
- Those derived from natural ligands:
- Many solid cancers are from overexpression of the G-coupled protein receptors (GPCR), including the somatostatin receptor.
- Octreotide is a somatostatin receptor agonist with D-amino acids and selective binding.
Gastrin-releasing peptide derivatives.
- Overexpression of the gastrin releasing peptide receptor seems to be associated with prostate and breast cancers, with bombesin analogues showing high affinity to the receptor.
Peptides that target the tumor microenvironment.
Peptides that target tumor pH and temperature.
- Some peptides adopt new conformations with pH or temperature changes, resulting in improved affinity.
Melanocortin-1 receptor (MC1R) ligand mimetics
- An overexpression of MC1R is seen in many melanomas. α-MSH derivatives may be useful in melanoma imaging.
- Those identified using combinatorial chemistry:
Peptides that target the tumor’s vascular system.
- Tumors affect angiogenesis and VEGF-A release.
Peptides that target the tumor blood supply.
- The RGD peptides, or integrins, are endothelial binding peptides that are overexpressed during angiogenesis. There are many applications for RGD peptide derivatives, including antagonist drugs, tumor imaging, and tumor uptake.
Peptides that target the lymphatic vessels of the tumor.
- Peptides specific to the lymphatics of certain cancers, such as LyP-1 peptide (CGNKRTRGC), target the connection between the tumor and the lymph nodes without binding to blood vascular endothelial cells.
Peptides that target the macrophages.
- Depleting the M2 macrophages with a targeting peptide can help slow tumor growth.
- Lymph targeting peptides that also are cell-penetrable, including the cyclic iRGD peptide, H-(CRGDKGPDC)-NH2, may slow tumor metastasis.
Peptides that target malignant brain tumors
- The CooP peptide, CGLSGLGVA, targets malignant brain tumors.
- Fibronectin binding peptides may also be useful in brain tumor imaging, since fibronectin plays a role in tumor growth.
As you can see, peptides can play a major role in targeting cancer. Their small size and ease of adding modifications, make them ideal candidates for cancer therapies and screening.1
- V. Le Joncour & P. Laakkonen, Bioorg & Molec Chemistry, 26, 2797 (2018).