| Description |
Peptides are a powerful class of therapeutics with high potency, high specificity, low immunogenicity, and effective methods of discovery. However, peptides often possess limitations including degradation by proteases, rapid clearance by renal filtration, and difficulty passing through membranes. The Kay lab at the University of Utah has applied the benefits of peptide design to tackling the problem of HIV-1 transmission. In this dissertation I describe the discovery of our lead peptide candidate, PIE12, including its optimization by mirror-image phage display, its potency enhancement by defined geometric linkages and lipid conjugation, its engineered ability to prevent HIV-1 resistance, and finally the optimization of its pharmacokinetic properties. These efforts have overcome the common limitations of peptide therapeutics and produced an ideal preclinical candidate for the treatment and prevention of HIV/AIDS. The first chapter examines the scope of the HIV pandemic, describes HIV-1's susceptible target for which we developed PIE12, and includes a brief examination of the current state of the peptide therapeutic field. The second chapter reviews methods of peptide discovery that enable protease resistance, including a discussion of well-validated techniques like mirror-image phage display followed by a review of several emerging technologies. The third chapter reveals how the aforementioned techniques were utilized in the discovery of PIE12, including early efforts to link PIE12 peptides together in order to improve potency. The fourth chapter completes this story, illuminating our efforts to optimize the linkages between PIE12 peptides in order to increase potency, and includes information on potency-enhancing membrane-tethering moieties. The fifth chapter describes our efforts to make potent PIE12-conjugates suitable for subcutaneous delivery, including new conjugate designs and detailed evaluation of their half-life-improving properties. The final chapter discusses future directions and new opportunities revealed to us by the body of this work. iv |
