期刊
CHEMICAL SCIENCE
卷 12, 期 10, 页码 3526-3543出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0sc03603j
关键词
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资金
- UT MDACC Startup Funds
- Cancer Prevention and Research Institute of Texas (CPRIT) Individual Investigator Research Award [RP200166-IIRA]
- University of Texas MD Anderson Cancer Center Institutional Research Grant (IRG) Program
- MD Anderson SPORE in Ovarian Cancer NCI [P50 CA217685, R01 CA135354, R21 CA181994, R01 GM127585]
- MD Anderson CCSG grant [NCI P30 CA 16672]
- CPRIT Early Translational Research Award [RP170333]
- National Foundation for Cancer Research
- UT MDACC Moonshot Knowledge Gap Pilot Project
- [T32CA196561]
- [F32EB024379]
Autophagy induction has been found to play a crucial role in the development of treatment resistance and dormancy in various cancer types. Current autophagy inhibitors, such as chloroquine and hydroxychloroquine, face challenges of poor pharmacokinetics and high toxicity at therapeutic dosages. Through the use of Scanning Unnatural Protease Resistant (SUPR) mRNA display, macrocyclic peptides targeting the autophagy protein LC3 were developed, showing promising results in sensitizing platinum-resistant ovarian cancer cells to chemotherapy. These peptides disrupted protein-protein interactions and inhibited autophagic flux, leading to significant tumor growth inhibition in mouse models of metastatic ovarian cancer.
In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Unfortunately, chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B-two essential components of the autophagosome maturation machinery-with mid-nanomolar affinities and disrupted protein-protein interactions (PPIs) between LC3 and its binding partners in vitro. The most promising LC3-binding SUPR peptide accessed the cytosol at low micromolar concentrations as measured by chloroalkane penetration assay (CAPA) and inhibited starvation-mediated GFP-LC3 puncta formation in a concentration-dependent manner. LC3-binding SUPR peptides re-sensitized platinum-resistant ovarian cancer cells to cisplatin treatment and triggered accumulation of the adapter protein p62 suggesting decreased autophagic flux through successful disruption of LC3 PPIs in cell culture. In mouse models of metastatic ovarian cancer, treatment with LC3-binding SUPR peptides and carboplatin resulted in almost complete inhibition of tumor growth after four weeks of treatment. These results indicate that SUPR peptide mRNA display can be used to develop cell-penetrating macrocyclic peptides that target and disrupt the autophagic machinery in vitro and in vivo.
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