How do therapeutic peptide and peptide-drug conjugate (PDC) cell therapy drugs work?

In summary

Peptide therapeutics are small chains of amino acids (basically mini proteins) that can be used to treat diseases. They’re made of the same monomer (amino acid) as proteins, but proteins are much larger polymers than peptide drugs. The body naturally creates peptides for a bunch of different functions, so it’s a versatile way to create drugs whose presence creates signals for cell processes. Peptides can also be used for cancer therapy in a modality called peptide-drug conjugates, where the peptide, when attached to a cytotoxic active ingredient, is used to find and destroy tumor cells.

In depth

Hello and welcome back! After a very busy month and a half, let’s talk about peptide therapeutics.

In Boston, I see a ton of peptide therapeutic start ups popping up, but the actual peptide modality has been around for quite a while. Insulin is probably one of the most recognizable therapeutic peptides available on the market, but other commercially available, therapeutic peptides are used to treat bowel diseases, hereditary angioedema, cancer (using peptide-drug conjugates), and even HIV treatment. In terms of therapeutic modality sizing, peptides are the intermediate between small molecules (oligonucleotides) and large molecules (proteins). They’re made of the same monomer (amino acid) as proteins, but they’re a different class of medicine, because proteins are much larger polymers (thousands of amino acids) than peptide drugs (usually less than 100 amino acids). They also have increased stability and reduced immunogenicity because of their sizes, so relative to proteins, therapeutic peptides are a safer therapeutic modality on average. Check out the diagram below from a peptide manufacturer for differences between small molecules, peptides, and proteins:

A comparison between small molecule, peptide, and protein therapeutic characteristics

Since there’re so many applications to therapeutic peptides, I’ll focus on the peptide hormone applications. To understand how therapeutic peptides work, we need to go into a little bit about cell signaling. I like to think about cells like little radio towers, constantly transmitting and accepting signals to others towers. In one of the best understood cases, cells send chemical messages called ligands to other cells, and the cell that receives this message uses one of its hundreds of specialized receptors. Each cell type (such as pancreatic cells, neurons, and liver cells) has different kinds of receptors, because each message is designed to insight a different cellular response! So, in many cases, therapeutic peptides can act as these ligands that cue a certain cell type to perform a specific function.

Like I mentioned earlier, therapeutic peptides can be used for cancer treatment, and some therapeutic peptide hormones are used for breast and prostate cancer, but the common modality structure is different from peptide hormones. Remember when we talked about synthetic peptides being the ligands for certain cell receptors? In a peptide-drug conjugate, the peptide is that ligand, and using a linker molecule, the peptide is attached to the cytotoxic drug (usually a chemotherapy like camptothecin or paclitaxel). In a peptide-drug conjugate, the peptide is actually called the “homing peptide,” because the peptide essentially finds the tumor cell so that the cytotoxic, active ingredient can kill only the tumor cell. And this type of drug is really revolutionary, because many of the traditional chemotherapeutics are administered systemically, so every cell, whether it’s a tumor cell or not, is exposed to the cytotoxicity.

Now, therapeutic peptides don’t exactly classify as gene therapy, and let me explain why. When we talked about ASOs and siRNA, we had modalities that were directly involved in gene regulation by say repressing translation. However, these therapeutic peptides aren’t exactly working within the central dogma–they don’t directly interfere with the DNA or RNA processes we think of with traditional gene therapy. I like to think of therapeutic peptides working more in parallel to gene therapy, because it’s helping the cell to insight a favorable response by exposing the cell to these artificial signals. For example, a study in the Journal of Medical Endocrinology found that the adrenocorticotropic hormone therapeutic peptide has been shown to regulate gene expression in adrenal cells. It’s not quite working on the DNA and RNA aspect of gene regulation, but it’s working in parallel on the cell side.

There have been recent applications of peptides to gene therapy, though. Because the amino acids in the peptide oligomers are polar, changing the polarity of the peptide solution can cause the peptide to create a micelle which encapsulates the “active ingredient,” either DNA or RNA. Check out this review of peptide-based gene delivery mechanisms!

In literature

These are some of my favorite papers to help you learn more about therapeutic peptides!

Leave a Reply

Please log in using one of these methods to post your comment: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s