Rational design of peptide affinity agents: applications in elucidating biomolecular interactions, drug delivery, and bioprocessing

Abstract

Over the next half-century advances within the fields of biotechnology and medicine must be made to address the critical issues facing society. As biopharmaceuticals continue to gain dominance in the pharmaceutical field with the growth of both the biosimilars market and increase in the number of novel biopharmaceutical therapies in development, disruptive technologies will need to be developed. The delivery of biopharmaceutical molecules within the body and their bioprocessing will take center stage with this anticipated growth of the biopharmaceuticals industry. From the drug delivery perspective, poor tissue penetration and low bioavailability of biopharmaceuticals motivate the need to better understand protein-protein interactions, while the complex product microheterogeneity of biopharmaceuticals places significant purification burden on the bioprocessing industry. Peptide affinity agents offer potential solutions to these issues across a variety of fields, with applications in elucidating biomolecular interactions, drug delivery, and bioprocessing. Utilization of rational design principles allows large libraries of peptide candidates to be generated and screened via high-throughput microarray technologies. An initial analysis of the protein-protein interactions found within the central nerv-ous system, specifically focused on the interactions of the tight-junction protein claudin-5. These studies revealed dominant trans-interactions between the two extracellular loops of claudin-5. This elucidated interaction was utilized in the subsequent design of Permeability Enhancing Peptides for the Disruption, Attenuation, & Recovery of Tight-junctions (PEPDARTs). PEPDARTs aim to alter the permeability profile of the blood-brain barrier to afford increased bioavailability of small-molecule drugs and biopharmaceuticals. Further extension of the rational design of peptide affinity agents into the field of bioprocessing permitted the design of peptide affinity ligands for the purification of a clinically utilized therapeutic enzyme. The methodologies developed in this study have since been extended to a multi-university and organization collaboration aimed at providing life-saving biopharmaceuticals on-demand in remote corners of the world. Finally, the developed peptide affinity ligand methodologies have been explored for extension into the fields of regenerative and personalized medicine for the bioprocessing of whole cells, such as induced pluripotent stem cells or stem cell derived cell types.