MSGID: 1:317/3 63edb16b   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Scientists reengineer cancer drugs to be more versatile    
    Control of specific gene-expression pathways could spur better treatment   
   of many diseases    
      
     Date:   
         February 15, 2023   
     Source:   
         Rice University   
     Summary:   
         Scientists enlist widely used cancer therapy systems to control   
         gene expression in mammalian cells, a feat of synthetic biology   
         that could change how diseases are treated.   
      
      
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   FULL STORY   
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   Rice University scientists have enlisted widely used cancer therapy   
   systems to control gene expression in mammalian cells, a feat of synthetic   
   biology that could change how diseases are treated.   
      
      
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   The lab of chemical and biomolecular engineer Xue Sherry Gao discovered   
   a way to further tap the therapeutic potential of proteolysis targeting   
   chimeras (PROTACs), small molecules that are used as effective tools for   
   treating cancer, immune disorders, viral infections and neurodegenerative   
   diseases.   
      
   Gao and collaborators reengineered the PROTAC molecular infrastructure and   
   showed it can be used to achieve chemically induced dimerization (CID),   
   a mechanism by which two proteins bind together only in the presence of   
   a specific third molecule known as an inducer. The research is described   
   in a study published in the Journal of the American Chemical Society.   
      
   "The novelty of this is the extent of control that combining these two   
   mechanisms gives us over inducing gene activation at desired locations   
   in the body and for desired durations," Gao said.   
      
   "Small molecules can act as a switch to turn gene expression on and off,"   
   she said. "Temporal control is a result of the fact that small molecules   
   are metabolized by living organisms. What this means is that you can   
   schedule for a certain gene to be expressed for a certain amount of time.   
      
   "In terms of spatial control, we can deliver the system only to the   
   organ or site of the body where it is needed," Gao continued. "You don't   
   need to have the medication go through your whole body and generate   
   unnecessary and harmful toxicity."  The CID mechanism is a key part of   
   many biological processes, and over the past two decades scientists have   
   devised a host of ways to engineer it to serve medical, research and   
   even manufacturing needs. The development highlights the growing impact   
   of synthetic biology, which takes an engineering approach to biological   
   systems, repurposing their mechanisms to harness new resources.   
      
   Sirolimus, formerly known as rapamycin. is an example of a molecule that   
   can act as an inducer and form CID systems with multiple cell pathways   
   in the body.   
      
   Discovered in 1972 in soil bacteria on Easter Island, the compound has   
   been used as an antitumor and immunosuppressant drug. More recently, it   
   was touted as a potential anti-aging drug after researchers discovered   
   it could interfere with a cellular pathway that activates lysosomes,   
   organelles responsible for cleaning up damaged cells.   
      
   "CID systems are attractive tools because they enable precise control over   
   molecular interactions, which in turn can activate or inhibit biological   
   outcomes, such as, for example insulin production in a diabetic patient   
   or tumor growth in a cancer patient," Gao said.   
      
   "Right now there are only a limited number of functional and efficient   
   CID systems," she added. "I wanted to address this unmet need. I saw   
   PROTACs, which are already being used with good results as therapies,   
   as an opportunity to expand the CID toolbox."  PROTACs work by targeting   
   specific proteins, such as those found in a tumor, causing them to   
   disintegrate. One side of the molecule binds to a targeted harmful   
   protein, another side flags down a specific enzyme that initiates protein   
   degradation and a third element connects the two sides together.   
      
   "You can think of this mechanism as similar to a smart missile that relies   
   on a sensor to track its target," Gao said. "The vocabulary is suggestive   
   in this sense, too, since the protein you want to destroy is called a   
   'target protein,' and the part of the PROTAC system that binds to the   
   target protein is called a 'warhead.' We are hijacking this system to   
   control gene expression instead."  The advantage of PROTACs over other   
   drugs is that they can be effective in small doses and do not lead to   
   the development of drug resistance. There are over 1,600 PROTAC small   
   molecules approved for cancer therapy, acting on more than 100 human   
   protein targets.   
      
   "PROTACs are very efficient and act with great specificity against   
   oncogenic proteins, which are proteins encoded by certain activated or   
   dysregulated genes that have a potential to cause cancer," Gao said. "We   
   wanted to harness that efficiency and precision and put it to work in   
   a new way. We redesigned PROTAC from a protein-degradation system to a   
   gene-activation system.   
      
   "Ultimately, I hope this will prove useful in the context of treating   
   real diseases," she continued. "The ability to regulate when and   
   where genes are activated in the body could help solve a wide range   
   of medical problems. My main goal with this project is to have a small   
   molecule-controlled gene expression system, including the CRISPR genome   
   editors."  Gao is Rice's T.N. Law Assistant Professor of Chemical and   
   Biomolecular Engineering and an assistant professor of bioengineering   
   and chemistry. The study was developed in collaboration with the Zheng   
   Sun lab at Baylor College of Medicine.   
      
   The National Science Foundation (2143626), the Robert A. Welch   
   Foundation (C- 1952), the National Institutes of Health (HL157714,   
   HL153320, DK111436, AG069966, ES027544), the John S. Dunn Foundation,   
   the Clifford Elder White Graham Endowed Research Fund, the Cardiovascular   
   Research Institute at Baylor College of Medicine, the Dan L. Duncan   
   Comprehensive Cancer Center (P30CA125123), the Specialized Programs of   
   Research Excellence (P50CA126752), the Gulf Coast Center for Precision   
   Environmental Health (P30ES030285) and the Texas Medical Center Digestive   
   Diseases Center (P30DK056338) supported the research.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Human_Biology # Personalized_Medicine #   
                   Diseases_and_Conditions # Medical_Topics # Lung_Cancer #   
                   Gene_Therapy # Genes # Cancer   
       * RELATED_TERMS   
             o Gene_therapy o Bioinformatics o Cancer o Prostate_cancer o   
             BRCA1 o Stem_cell o Embryonic_stem_cell o Human_biology   
      
   ==========================================================================   
   Story Source: Materials provided by Rice_University. Original written   
   by Silvia Cernea Clark.   
      
   Note: Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Dacheng Ma, Qichen Yuan, Fei Peng, Victor Paredes, Hongzhi Zeng,   
      Emmanuel   
         C. Osikpa, Qiaochu Yang, Advaith Peddi, Anika Patel, Megan S. Liu,   
         Zheng Sun, Xue Gao. Engineered PROTAC-CID Systems for Mammalian   
         Inducible Gene Regulation. Journal of the American Chemical Society,   
         2023; 145 (3): 1593 DOI: 10.1021/jacs.2c09129   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/02/230215143648.htm   
      
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