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Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
A designed cyclic peptide based on Trastuzumab used to construct peptide-drug conjugates for its HER2-targeting
Jiaqi Zhou1, Yuxing Zou1, Yan Cai1
1Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Abstract:
Human epidermal growth factor receptor 2 (HER2) has been recognized as an important therapeutic target for its overexpression in many cancers. Trastuzumab is a monoclonal antibody targeting HER2, which has been approved by FDA to treat HER2-positive cancer. In this research, cyclic peptide Cyclo-GCGPep1 was designed based on the binding mode between antibody and HER2 protein in silico, which has been confirmed possessing good affinity with HER2. Cyclo-GCGPep1 was also used to construct peptide-drug conjugates with Camptothecin. Biological evaluations demonstrated that Conjugate 1 has a good antiproliferative activity on SK-BR-3 and NCI-N87 cells. Conjugate 1 retained the pro-apoptotic and Topo I inhibitory ability of Camptothecin. Meanwhile, it has good targeting ability towards HER2-positive cells with the help of Cyclo-GCGPep1. It also has better permeability in the tumor spheroid model than Camptothecin. In summary, the design of cyclic peptide derived from antibody is of significance for the discovery of targeting peptides and Conjugate 1 is expected as a good therapeutic agent for HER2-positive cancers.
Insights
A novel cyclic peptide, Cyclo-GCGPep1, targets HER2-positive cancers. Peptide-drug conjugates show potent antiproliferative activity and enhanced tumor cell permeability, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Human epidermal growth factor receptor 2 (HER2) is a key therapeutic target in various cancers.
- Trastuzumab, an FDA-approved anti-HER2 monoclonal antibody, is used for HER2-positive cancers.
- Targeted therapies aim to improve efficacy and reduce side effects in cancer treatment.
Purpose of the Study:
- To design a novel cyclic peptide targeting HER2 based on antibody-HER2 interactions.
- To develop peptide-drug conjugates using the cyclic peptide and Camptothecin.
- To evaluate the efficacy and targeting ability of the conjugate in HER2-positive cancer models.
Main Methods:
- In silico design of cyclic peptide Cyclo-GCGPep1 based on HER2-antibody binding.
- Construction of peptide-drug conjugates (Conjugate 1) with Camptothecin.
- In vitro antiproliferative assays on HER2-positive cell lines (SK-BR-3, NCI-N87).
- Evaluation of apoptosis induction and Topoisomerase I inhibition.
- Assessment of tumor targeting and permeability in a tumor spheroid model.
Main Results:
- Cyclo-GCGPep1 demonstrated good affinity for HER2.
- Conjugate 1 exhibited significant antiproliferative activity against SK-BR-3 and NCI-N87 cells.
- Conjugate 1 retained the therapeutic properties of Camptothecin, including apoptosis induction and Topo I inhibition.
- The peptide facilitated HER2-positive cell targeting and showed improved tumor spheroid permeability compared to Camptothecin.
Conclusions:
- The design of antibody-derived cyclic peptides is a valuable strategy for discovering targeted therapeutics.
- Conjugate 1 shows potential as an effective therapeutic agent for HER2-positive cancers.
- This approach offers a promising avenue for developing targeted cancer therapies with enhanced drug delivery.
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