(233c) Invited: 3D Bioprinting: A New Paradigm in Tissue Engineering

My laboratory has been interested, for the past 10 years, in developing stable, non-natural mimics of natural antimicrobial peptides, the latter of which are better termed host defense peptides (HDPs). For both HDPs and novel peptoid mimics we created and studied side by side, we found that the activity and selectivity of these antibiotic peptides depend on relative extents of net positive charge, hydrophobicity, amphipathicity, and in some cases, their self-association into meta-stable assemblies that dissemble upon encountering electronegative cell membranes. We completed a series of biophysical mechanistic studies utilizing HDPs and peptoids comprising orthogonal activity/selectivity profiles, displaying either high (or low) activity and high (or low) selectivity, providing a grid of mechanistic data that facilitates comparisons of selective and non-selective HDPs. Vesicle leakage, membrane depolarization, and TEM yielded surprising information concerning interrelationships between mechanisms by which peptide and peptoid variants exert damaging effects on pathogens vs. mammalian cells.

         Unexpected insights into biology and physiology followed a realization that our most active antibiotic peptoids invariably had concomitant cytotoxicity; we discovered that this is also true of important classes of HDPs.  And as many researchers have learned but few have reported in the literature given that it is a negative result from a drug development standpoint, high HDP selectivity in mammalian cell culture does not necessarily nor at all reliably predict low toxicity in living mammals.

         An important result of our studies was that we have learned and will explain that bacteria, fungi, and mammalian cells have evolved powerful, complex mechanisms of resisting and recovering from different types of HDP-induced damage; some are internal to the cells, while others involve well-known extracellular constructions.

         I will describe striking mechanistic similarities between antibacterial and cytotoxic activities of peptoid HDP mimics and of natural HDPs. The latter are phylogenetically ancient innate immune effectors.  Particular peptides constitute one-of-a-kind weapons in the human proteomic arsenal, while also playing indispensible pleiotropic roles at many levels in mammalian physiology.  Guided by these insights and the clinical literature, I hypothesize a central role for HDPs in the etiology of human degenerative diseases, including Alzheimer’s and other amyloid diseases (atherosclerosis, diabetes, and other maladies) as a consequence of the HDPs’ interrelated, highly potent mechanisms of action—both beneficial and damaging—which are profoundly concentration-dependent.   Extrapolation of these insights predict that a major key to understanding human health and disease will be gaining a deep understanding of how human lifetime experiences dictate and control temporal and spatial dynamics and concentrations of HDPs and the nanoparticle complexes that they form within tissues and organs of the human body.