New methods in peptide mimicry

点击翻译按钮获取中文摘要

Peptides and more importantly their related mimics, both serve as effective drugs in clinic today. Prominent traditional examples include oxytocin, insulin, cyclosporin and salmon calcitonin, which are widely used in childbirth, diabetes, immunosuppression and osteoporosis, respectively. At present more than 40 peptides are marketed worldwide, around 270 peptides are in clinical phase testing, and about 400 are in advanced preclinical phases (Marx, V. "Watching Peptide Drugs Grow Up" Chem. & Eng. News Mar. 14, 2005, Vol 83 (11) pp. 17-24). A new age of peptide-based pharmaceutical agents is emerging from fertile studies in genomics and proteomics. Inherent drawbacks to peptide structures have, however, required development of novel tools for studying peptide interactions and new peptide mimics with improved pharmacological properties to surmount the necessary hurdles to enter into clinic. Such has been the case for new peptide-based drugs, such as the GnRH antagonist Zoladex for treating prostate cancer, which was made more resistant to enzyme metabolism by incorporating an aza-amino acid at the C-terminal residue. Similarly, Symlin a new drug for the treatment of diabetes contains a synthetic analog of a naturally occurring human peptide hormone, amylin. Promising peptide-based drugs for the future include vaccines against various cancers and malaria as well as novel antimicrobial agents to fight organisms exhibiting resistance to present day drugs. The process from peptide to drug is, however, particularly challenging and diagnostic tools for dissecting the native peptide are required to furnish information for recreating elements required for receptor recognition and signal transduction. This proposal focuses on the creation of such tools and their use to construct mimics exhibiting higher potency, enhanced metabolic stability and improved biological availability relative to the native peptide. Because the number of peptides serving as lead structures for drug discovery continues to grow, the proposed research on new strategies for creating peptide mimics is positioned to provide valuable insight and practical leads for the future production of new drugs, biopolymers and materials.