The team employed Transcription Block Survival assay to test multiple peptides for their ability to disable transcription factors.
In a first, scientists have identified promising drug candidates that can permanently disable a key cancer protein once deemed untreatable—a discovery that could revolutionize cancer treatment .Using an innovative screening method, the researchers discovered peptides—short chains of amino acids—that can irreversibly inhibit this cancer protein within cells.
Transcription factors are proteins that serve as master regulators of gene expression. They play a crucial role in cancer progression. However, efforts to develop small-molecule drugs to target these proteins have largely been unsuccessful.To address this issue, scientists are increasingly turning to peptides as a potential solution for tackling these cancer-related proteins.Now, researchers from the University of Bath have developed a groundbreaking approach that enables peptides to bind to cJun, a key cancer-driving transcription factor, inside cells.To achieve this, the team employed a novel drug discovery screening platform, known as the Transcription Block Survival assay, to test multiple peptides for their ability to disable transcription factors.The study builds on researchers’ previous study in which they identified reversible inhibitors of cJun.How the inhibitor blocks cancer proteincJun consists of two identical halves. In cancer patients, these halves bind to opposite sides of the DNA strand, altering gene expression in the process. When overactive, cJun can drive uncontrolled cell growth.To counter this, the peptide inhibitor binds to one half of cJun, preventing it from pairing and attaching to DNA. Once the peptide attaches to the transcription factor, the researchers modified it to bind irreversibly.“The inhibitor works a bit like a harpoon that fires across to the target and won’t let go – it grips the cJun tightly and stops it from binding to the DNA,” Dr. Andy Brennan, first author of the study, said in a press release.“We’d previously identified reversible inhibitors but this is the first time we’ve managed to block a transcription factor irreversibly with a peptide inhibitor.”Screening for effective cancer drug candidatesFor the Transcription Block Survival assay, researchers placed special landing spots for the cJun protein inside an important gene in lab-grown cells. When cJun attaches to these spots, it switches off the gene, causing the cell to die. However, if a peptide inhibitor blocks cJun, the gene remains active, allowing the cell to survive.“Many drug candidates that are effective in vitro turn out to be toxic or don’t penetrate cancer cells at all. “However, our platform screens for peptide activity directly in the cell, overcoming many common challenges faced by drugs based on small molecules or antibodies,” Jody Mason, CSO of Revolver Therapeutics and Professor of Biochemistry at the university said.The researchers explained that the screening process evaluates the inhibitor’s activity within a real cell environment, which contains proteases and other proteins that might interfere with peptide function.They also expressed hope that this technology could, in the future, help identify promising drug candidates for previously “undruggable” targets.After confirming that the inhibitors can enter cancer cells and remain active, the scientists now need to demonstrate their effectiveness in preclinical cancer models.The research, which was partly funded by the Medical Research Council and Biotechnology and Biological Sciences Research Council, has been published in Advanced Science.
Cjun Protein Drug Discovery Gene Expression Irreversible Binding Oncology Research Peptide Inhibitors Screening Assay Targeted Therapy Transcription Factors
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