Norman Metanis, PhD
Project Title
Targeting GPx4 in Cancer using Mirror-Image RaPID Technology
About the Investigator
Norman Metanis is a Professor of Chemistry whose research lies at the interface of medicinal chemistry, chemical biology, and therapeutic peptide design. His laboratory specializes in chemical protein synthesis and the development of stabilized peptide and protein therapeutics targeting challenging disease-relevant proteins. He has made key contributions to peptide drug development, including stabilized analogues of calcitonin for osteoporosis, novel insulin variants with improved stability and function, and advanced peptide-based strategies for cancer therapy. More recently, his group developed the MI-RaPID platform for discovering highly stable macrocyclic D-peptide inhibitors targeting cancer-associated proteins, addressing critical unmet needs in oncology drug discovery.
About the Research
This Israel Cancer Research Fund (ICRF) proposal aims to develop a new class of stable, selective, and biologically active macrocyclic D-peptide inhibitors targeting glutathione peroxidase 4 (GPx4), a central regulator of ferroptosis and a key survival factor in multiple aggressive and therapy-resistant cancers. GPx4 is frequently overexpressed in tumors and protects cancer cells from lipid peroxidation, an induced cell death, making it an attractive yet challenging therapeutic target. Existing GPx4 inhibitors are limited by poor selectivity, chemical instability, toxicity, and unfavorable pharmacokinetics.
To overcome these limitations, the proposed research leverages the laboratory’s proprietary Mirror-Image Random Nonstandard Peptides Integrated Discovery (MI-RaPID) platform. This approach combines chemical protein synthesis of mirror-image D-proteins with macrocyclic peptide libraries to discover highly stable, high-affinity D-peptide inhibitors. The project will involve chemical synthesis of full-length D-GPx4, RaPID-based selection of cyclic peptide binders, synthesis of mirror-image macrocyclic D-peptides, and comprehensive evaluation of their stability, binding affinity, enzymatic inhibition, and ability to induce ferroptosis in cancer cell models.
The expected outcome is the identification of first-in-class GPx4-targeting macrocyclic D-peptides with superior selectivity, proteolytic resistance, and therapeutic potential. Beyond GPx4, this work will establish MI-RaPID as a broadly applicable platform for targeting intracellular cancer proteins previously considered inaccessible to biologics. In the long term, this research may enable the development of safer and more effective ferroptosis-based cancer therapies, addressing a critical unmet need in oncology.
