Project Grant 2440912

CAREER: DESIGNING MIXED-MODE PURIFICATION MATERIALS FOR BIOMANUFACTURING AND ELUCIDATION OF PROTEIN ADSORPTION BEHAVIORS -PROTEIN-BASED THERAPEUTICS HAVE REVOLUTIONIZED THE TREATMENT OF DISEASES WITH HISTORICALLY POOR PROGNOSES, INCLUDING MANY ONCOLOGICAL, NEUROLOGICAL, AND INFECTIOUS CONDITIONS. THESE ADVANCED THERAPEUTICS ARE PRODUCED IN ENGINEERED CELLS. HOWEVER, THE CELLS ALSO PRODUCE UNWANTED IMPURITIES ALONGSIDE THE THERAPEUTIC, INCLUDING INFECTIOUS VIRUSES, UNWANTED PROTEINS AND DNA, AND MISFORMED PRODUCTS. THESE IMPURITIES MUST BE REMOVED TO ENSURE PATIENT SAFETY AND TREATMENT EFFICACY. MOST CURRENT SEPARATION METHODS ARE NOT DESIGNED TO PURIFY THESE EMERGING THERAPEUTICS, CREATING BOTTLENECKS IN DRUG DISCOVERY AND MANUFACTURING PIPELINES. MORE EFFECTIVE SEPARATION METHODS COULD ACCELERATE DEVELOPMENT AND ACCESSIBILITY OF THESE MEDICINES AND REDUCE COSTS FOR PATIENTS AND PHARMACEUTICAL COMPANIES. THIS PROJECT WILL DESIGN INNOVATIVE, BIOLOGY-INSPIRED ADSORPTIVE SEPARATION MATERIALS USING PEPTIDES, A TYPE OF BIOPOLYMER, TO PURIFY NEW MEDICINES FROM CONTAMINANTS. KNOWLEDGE GAINED ABOUT THE MATERIALS WILL BE USED TO BUILD AN ENGINEERING TOOLBOX TO OPTIMIZE THE DESIGN OF HIGHLY EFFICIENT SEPARATION MATERIALS AND PREDICT THEIR PERFORMANCE IN MANUFACTURING. THE PROJECT WILL ALSO HELP TRAIN A DOMESTIC WORKFORCE EQUIPPED TO TACKLE THE CHALLENGES ASSOCIATED WITH MANUFACTURING THESE NOVEL THERAPEUTICS. AN ANNUAL SUMMER WORKSHOP FOR ENGINEERING STUDENTS WILL BE ESTABLISHED, OFFERING HANDS-ON TRAINING IN BIOMANUFACTURING PROCESSES AND CUTTING-EDGE MODELING TOOLS TO FACILITATE RAPID AND RELIABLE DESIGN OF THESE CRITICAL SYSTEMS. THIS PROJECT WILL LEVERAGE RATIONALLY DESIGNED SHORT PEPTIDES TO ADVANCE THE MOLECULAR UNDERSTANDING OF PROTEIN ADSORPTION ONTO FUNCTIONALIZED SURFACES AND ESTABLISH DESIGN RULES LINKING THE CHEMISTRY AND ARCHITECTURE OF MIXED-MODE PEPTIDE LIGANDS FEATURING SYNERGISTIC INTERACTION MODES TO PROTEIN ADSORPTION BEHAVIORS. USING THESE MATERIALS, THE INVESTIGATOR WILL DETERMINE HOW FACTORS SUCH AS GRAFTING DENSITY, LIGAND FLEXIBILITY, ION TYPE, AND THE SPATIAL ARRANGEMENT OF CHARGE AND HYDROPHOBIC CHEMICAL GROUPS INFLUENCE PROTEIN ADSORPTION IN CHROMATOGRAPHIC SYSTEMS AND OTHER FUNCTIONALIZED SURFACES. FURTHERMORE, THIS PROJECT WILL QUANTITATIVELY EXAMINE HOW THESE LIGAND PROPERTIES DICTATE WHICH PROTEIN SURFACE CHARACTERISTICS GOVERN INTERACTIONS IN NON-SPECIFIC ADSORPTION SYSTEMS. TAKEN TOGETHER, THESE INSIGHTS WILL ENABLE THE IDENTIFICATION AND SYNTHESIS OF A SMALL SET OF ORTHOGONALLY SELECTIVE MIXED-MODE CHROMATOGRAPHIC RESINS CAPABLE OF EFFICIENTLY PURIFYING A WIDE RANGE OF PROTEIN THERAPEUTIC MODALITIES. ADDITIONALLY, THIS PROJECT WILL ESTABLISH A PREDICTIVE PROCESS DESIGN TOOL BY CREATING A NEW MODEL FOR STUDYING AND TRACKING INDIVIDUAL HOST CELL PROTEIN TRANSPORT AND ADSORPTION IN THESE MATERIALS, ENABLING FULL IN SILICO DESIGN AND OPTIMIZATION OF SEPARATION PROCESSES FOR NEW THERAPEUTICS WITHOUT EXTENSIVE MODEL CALIBRATION. BEYOND ITS IMPLICATIONS FOR CHROMATOGRAPHIC SEPARATIONS AND STREAMLINING BIOMANUFACTURING WORKFLOWS, THIS WORK WILL ENHANCE THE UNDERSTANDING OF MIXED-MODE SURFACES IN BROADER APPLICATIONS, INCLUDING DRUG DELIVERY, BIOSENSING, AND BIOMATERIALS ENGINEERING. FURTHER, THIS RESEARCH PROGRAM WILL ESTABLISH A SUMMER WORKSHOP SERIES, CHROMATOGRAPHIC APPROACHES FOR MANUFACTURING PROTEIN BIOLOGICS (CAMPBIO), DESIGNED FOR UNDERGRADUATE ENGINEERING STUDENTS. THIS ANNUAL, WEEK-LONG PROGRAM WILL COMBINE LAB AND CLASSROOM-BASED LEARNING TO TEACH THE THEORY AND HANDS-ON APPLICATION OF MODELING AND PROCESS DEVELOPMENT FOR NON-TRADITIONAL PROTEIN THERAPEUTICS, DEVELOPING A WORKFORCE EQUIPPED TO SOLVE THE MANUFACTURING CHALLENGES ASSOCIATED WITH WIDENING THERAPEUTICS PIPELINES. THE DATA AND MODELS DEVELOPED THROUGH THIS RESEARCH AND CAMPBIO WILL BE LEVERAGED IN INTERACTIVE PROJECTS IN CHEMICAL ENGINEERING COURSES AT THE UNIVERSITY OF VIRGINIA, EXPOSING STUDENTS TO MANUFACTURING PROCESSES FOR NEW THERAPEUTIC MODALITIES. 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.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.