CAREER: Sequence Defined Peptoid Materials for Selective Biodegradation

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Non-Technical SummaryThe cells in the human body produce many types of molecules that degrade materials in their environment. These molecules can be small and non-specific, such as highly reactive radicals, or they can be large and more targeted, such as enzymes. The ability to sense which degradative molecules are present through simple bench top assays would enable more efficient characterization of disease states such as cancer or inflammation. This project will therefore study the degradation behavior of peptoids, a class of synthetic molecules that offers the potential to degrade selectively one type of biomolecule (radical species) but not another (enzymes). This selectivity will enable the design of peptoid-based sensors to non-invasively identify which degradative molecules are present in a biological environment, and this knowledge will also impact the design of new materials with well-defined degradation properties for use in biomedical implants. The proposed project will also include educational and outreach activities at the high school, undergraduate, and graduate student level to broaden the participation of diverse groups in biomaterials research. Specifically, it will develop a mentoring program to facilitate interactions among students from underrepresented populations in STEM at the annual Texas Biomaterials Day. Technical Summary Reactive oxygen/nitrogen species (ROS/RNS) and matrix metalloproteases (MMPs) are critical drivers of extracellular matrix remodeling, especially during disease and inflammation. Degradable peptides and proteins are commonly exploited as ROS and MMP sensors; however, a key challenge is cross-reactivity and limited selectivity toward one type of degradative species. Non-natural peptoids (or N-substituted glycines) offer an attractive platform with which to address these limitations due to their proteolytically-stable N-substituted polyamide backbone and potential selective susceptibility to ROS/RNS. In addition, peptoids preserve the monomer sequence definition of biomolecules but utilize an expanded class of side chain functionalities, which may access higher specificity to MMP degradation in hybrid substrates. The proposed research activities will combine synthesis with mass spectrometry and new degradation assays to: 1) define the selectivity and sensitivity of non-natural peptoids toward biologically relevant oxidative mechanisms of degradation, 2) determine monomer sequence effects on the specificity of hybrid substrate degradation by MMPs, and 3) assess peptoid-based biomaterials as platforms to simultaneously detect mixtures of ROS and MMPs. These studies will lead to fundamental insights regarding peptoid degradation behavior in complex biological environments and enable the development of peptoid-based sensors and materials for applications in tissue engineering, disease modeling, and diagnostic screening. In addition, the proposed educational activities will establish a new mentoring program to enhance the participation of students from Minority Serving Institutions and Historically Black Colleges and Universities in Texas at the annual Texas Biomaterials Day. Best practices from this mentoring program will be shared via webinar to facilitate the broad implementation of similar programs at the nine other Biomaterials Days across the country.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.