20] Design of minimum active fragments of biologically active peptides

Abstract

Publisher Summary This chapter discusses the design of minimum active fragments of biologically active peptides. Attempts to design biologically potent and receptor-selective peptides necessitate an understanding of the way the individual amino acids of the peptide contribute to its overall conformation at the biological receptor. This resulting bioactive conformation determines that individual amino acids of the peptide will interact with sites on the receptor; the remaining amino acids serve primarily a structural role to favor those conformations in which the critical residues are spatially situated for optimal interaction with the receptor. Often the amino acids that serve as structural elements can be deleted with the resulting peptide fragment retaining full or partial biological activity, although usually of reduced potency. It is possible to design biologically active peptides in a rational manner based on theoretical secondary structure prediction, spectroscopic analysis, such as nuclear magnetic resonance (NMR), and molecular modeling. Despite advances in the analysis of peptide conformation through these techniques, the effort put forth in their application is often in direct proportion to the size of the peptide under study. This is due to the considerable conformational flexibility shown by linear peptide hormones. Even constrained, cyclic disulfide-containing peptide hormones may possess considerable conformational freedom.