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Introduction: Targeted Therapies and the Evolution of Drug Design

Traditional therapies for cancer treatment usually focus on the characteristics of rapid cell replication. Examples include drugs like cyclophosphamide and cisplatin, which disrupt DNA replication in rapidly dividing cells, ultimately leading to cell death. However, normal cells such as red blood cells, epithelial cells, and hair matrix cells also divide rapidly, resulting in side effects like nausea, vomiting, hair loss, and reduced red blood cell counts.

To reduce such adverse side effects, scientists have developed drugs targeting specific proteins highly expressed in tumor cells. Imatinib was the first targeted drug for treating chronic myeloid leukemia and malignant gastrointestinal stromal tumors. Another notable example is Enhertu, a star among antibody-drug conjugates, which combines a HER2-directed antibody with a DNA topoisomerase I inhibitor to treat HER2-expressing solid tumors.

Among these targeted therapies, peptide drug conjugates (PDCs) have emerged as promising precision medicine tools due to their enhanced efficacy and safety profiles. PDCs combine the high specificity of macromolecules with the manufacturing simplicity of small molecules, making them an attractive therapeutic option

What Are Peptide Drug Conjugates?

PDCs consist of three main components: peptides, linkers, and drugs. These components work synergistically to deliver active compounds to target sites with high specificity. This modular design simplifies the development of new therapies.

Table 1. Classification of PDC Components

1. Peptides

Peptides in PDCs can serve as either target-specific ligands or cell-penetrating agents:

• Target-Specific Peptides: Direct PDCs to specific receptors overexpressed on target cells. A common example is the RGD tripeptide (arginine-glycine-aspartic acid), which targets αvβ3 integrin, frequently overexpressed in tumors.
• Cell-Penetrating Peptides: These peptides aid in cellular uptake due to properties like hydrophobicity, amphipathicity, and a net positive charge.

2. Linkers

Linkers connect peptides to drugs and control payload release. They can be:

• Non-cleavable Linkers: Remain intact after internalization (e.g., SMCC, EMCS).
• Cleavable Linkers: Activated by environmental triggers such as:
  • Enzymes: Common structures include Val-Cit and Gly-Gly-Phe-Gly.
  • Glutathione (GSH): Cleaved in the tumor microenvironment.
  • pH Sensitivity: Linkers like EMCH release drugs in acidic conditions.

3. Drugs/Payloads

Peptide-drug conjugate (PDC) payloads serve different therapeutic and diagnostic purposes depending on their mechanisms of action. Some common payloads include:

• MMAE, MMAF, and Doxorubicin: Cytotoxic agents that target rapidly dividing cancer cells by disrupting cell division or damaging DNA.
• Radioactive Nuclides: Target diseased tissues for destruction (therapeutic) or visualization (diagnostic) through radiation emission.
• Antibiotics and Imaging Molecules: Target bacterial infections or specific biological markers for therapeutic treatment or diagnostic imaging.

Applications and Benefits

The first FDA-approved drug was Lutathera, developed by Novartis, which targets somatostatin receptors using octreotate, minimizing damage to healthy tissues.

Beyond cancer, PDCs have diverse applications:

• Bacterial Infections: The Wang group developed a PDC targeting intracellular bacteria, using glycopeptides linked to P18 for reactive oxygen species generation.
• Diabetes Treatment: The Bao group conjugated sericin with tacrolimus using a succinate linker to manage diabetes.

Compared to ADCs, PDCs offer superior tissue penetration due to their smaller molecular weight. Table 2 highlights the differences between PDCs and ADCs:

Table 2. Comparison of PDCs vs. ADCs.

Challenges

Despite their advantages, PDCs face challenges such as:

• Short Half-Life: Peptides are prone to enzymatic degradation. Solutions include cyclization, chemical modifications, and using unnatural amino acids.
• Linker Instability: Premature cleavage in non-target tissues can limit efficacy, making careful linker design essential.

What Genscript can offer:

We provide comprehensive PDC synthesis services, including:

• Peptides: Custom synthesis with modifications like cyclization and azidation.
• Linkers: Both commercial and in-house linkers.
• Drugs: Non-cytotoxic agents (OEB level ≤ 3) and non-radioactive metals.

GenScript's expertise enables high-quality PDC development tailored to your specific research needs.

Learn more about our custom peptide synthesis services here.

References

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• [3] Keam S J. Trastuzumab Deruxtecan: First Approval[J]. Drugs, 2020, 80(5):501-508.
• [4] Cooper B M, Iegre J, O' Donovan DH, et. al. Peptides as a platform for targeted therapeutics for cancer: peptide-drug conjugates (PDCs)[J]. Chem Soc Rev, 2021, 50(3):1480-1494.
• [5] Ruan H, Chen X, Xie C, et. al. Stapled RGD Peptide Enables Glioma-Targeted Drug Delivery by Overcoming Multiple Barriers[J]. ACS Appl Mater Interfaces, 2017, 9(21):17745-17756.
• [6] Cai Q, Fei Y, Hu L, et. al. Chemotaxis-Instructed Intracellular Staphylococcus aureus Infection Detection by a Targeting and Self-Assembly Signal-Enhanced Photoacoustic Probe[J]. Nano Lett, 2018, 18(10):6229-6236.
• [7] Gao S, Li Y, Zhu T, et. al. rs-TAC PDC, a peptide drug-conjugate, for targeted delivery of tacrolimus and sericin alleviates podocyte injury in diabetic nephropathy[J]. Nano Today, 2024, 57.
• [8] Wang M, Liu J, Xia M, et. al. Peptide-drug conjugates: A new paradigm for targeted cancer therapy[J]. Eur J Med Chem, 2024, 265.

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