The Organic and Macromolecular Chemistry Program in the Chemistry Division at the National Science Foundation supports Professor Gregory Tew of the University of Massachusetts Amherst whose research will develop a novel class of biomimetic polymers with potent cell-penetrating activity. Preliminary work has demonstrated the ability to build cell-penetrating peptide, or protein transduction domain mimics. The comprehensive structure-activity relationship proposed is essential for gaining novel insight and laying a foundation for understanding the behavior of these unique molecules. This work will probe fundamental concepts between polymer chemistry and membrane transduction activity. And, since these molecules traverse the phospholipid membrane, new insights will be gained on how molecules bind with and move across this critically important biological barrier.
Research by Professor Tew combines state of the art organic and polymer chemistry with translocation across membranes and provides the opportunity to develop non-peptidic molecules that traverse the biological cell membrane barrier. This will have important applications in drug and non-viral gene delivery and also lay the foundation for learning how to target membranes within cells. Students trained within this multi-disciplinary proposal will become young scientists who are able to work across traditional disciplines. Professor Tew is an active participant in the National Organization for the Professional Advancement of Black Chemists and Chemical Engineers (NOBCChE) National Meetings. He conducted a workshop entitled "Landing Your First Tenure Track Faculty Position" at the 2006 National Meeting and was recently appointed to the technical programming committee. This successful workshop was scheduled again for the 2009 Annual Meeting. A peer-mentoring program was established within Polymer Science and Engineering (PSE) at the University of Massachusetts Amherst in 2005 which has received campus-wide recognition. The current proposal will be integrated into these on-going activities and specifically will be used as a platform for a new workshop at NOBCChE between students, the NOBCChE community, and industry focused on intellectual property and science. A provisional patent application has been filed covering the materials discussed in this proposal. It will be used as the platform to engage NOBCChE students in the topic of "translational research".
Nature uses cell penetrating peptides, or known as protein transduction domains, to enter cells upon command. The most famous example is the HIV-TAT protein from the HIV virus. This molecule is designed to circumvent the natural barrier present in all cells, the non-polar biological membrane. Since its discovery more than 20 years ago, extensive research has unraveled the key features that enable TAT to accomplish its job. Our research aims to capture these design principles in simpler molecules and then dramatically improve their properties so that better, more effective transduction tools are available for researchers world-wide. This is an important problem impacting many areas of basic and applied science. For example, with collaborators, we have shown the ability to access human primary T-cells in an unprecedented way leading to new insights in immuno-therapy. These breakthroughs were accomplished through funding of basic chemical sciences which enabled us to build, for the first time ever, new protein transduction domain mimics. This program developed a novel class of biomimetic polymers with potent cell-penetrating activity. Learning to build simple polymeric structures with protein-like activity is a critically important goal of modern science. We demonstrated the ability to build cell-penetrating peptide, or protein transduction domain, mimics, and assembled a comprehensive structure-activity relationship which is essential for gaining novel insight and laying a foundation for understanding the behavior of these unique molecules. The power of synthetic chemical diversity was demonstrated in a new discovery termed ‘self-activation.’ This new derivative carries its own hydrophobic groups that promote membrane translocation. Activity better than the gold standard was achieved. Funding this work allowed us to understand fundamental concepts between polymer chemistry and membrane transduction activity. Because these molecules transverse the phospholipid membrane, new insights were gained on how molecules bind with and move across this critically important biological barrier. This project combines state of the art organic and polymer chemistry with translocation across membranes. Educating students within this multi-disciplinary proposal will train young scientists with a broad technical background, ready to work across traditional disciplines. Further, workforce diversity is critical to maintaining America’s technological advantage; over the last five years, significant progress has been made in this area including a number of activities. To mention one, a peer-mentoring program was established within PSE which has received campus wide recognition.
