Preparation of large peptide libraries with one peptide per bead and their use for the discovery of peptides that bind to acceptors

V. J. Hruby, K. S. Lam, M. Lebl, W. Kazmlerski, E. M. Hersh, S. E. Salmon

Research output: Contribution to journalReview article

2 Scopus citations

Abstract

The authors developed a simple, highly reproducible, and synthetically clean method for preparing large, statistically diverse peptide libraries that can be used to discover ligands that will bind to acceptor molecules. Several other methods were developed using both biological and chemical methods to provide polypeptide diversity for a variety of applications (Scott and Smith 1990; Geysen et al. 1984; Fodor et al. 1991; Cwirla et al. 1990; Houghten et al. 1991; Oldenburg et al. 1992; Devlin et al. 1990; Scott et al. 1992; Cull et al. 1992; Brenner and Lerner 1992). These methods, and others to be discovered and developed, offer a number of opportunities to examine in new ways the fundamental issues of molecular recognition and the diversity of ways in which molecular recognition problems can be solved. With the availability of large, diverse peptide libraries, it is likely that, for the same acceptor site on a macromolecule, several different peptide structures will bind specifically to the same site with an affinity within a few orders of magnitude of each other. From these and other fundamental studies, it will be possible to address issues that could not be addressed before the availability of these libraries. For example, there are the basic questions of whether a small peptide of 5 to 15 residues can mimic a protein in its activities, whether a small linear peptide can serve as a mimotope for a discontinuous epitope on an antibody, or how big an area an inhibitor needs to recognize to be able to block the binding of the native ligand. The last question is an especially critical question for protein-protein interactions, where fairly large surface areas appear to be involved in molecular recognition. Can a small peptide serve as a competitive inhibitor for one of the sites of interaction to block the entire interaction? The answer is not clear. Another major issue is the difference between a peptide agonist and a peptide antagonist. It was suggested many years ago that peptide agonists and antagonists, even competitive ones, bind differently to the acceptor molecule (Meraldi et al. 1977). In this case, a peptide antagonist had greatly reduced flexibility relative to the agonist, and the specific induced rigidity was critical for antagonist bioactivity (Meraldi et al. 1977). Perhaps this effect of rigidity explains why small, relatively rigid peptidomimetics generally are antagonists of ligands for macromolecular acceptors. Another issue is how many different ways a particular molecular recognition problem can be solved. For example, it already has been noted that a particular recognition favors a particular primary sequence, called a consensus sequence, and that this sequence is conserved throughout evolution. The question is whether this sequence is truly 'essential' or whether some other sequence can serve the same purpose. This question now can be explored by constructing a large library of peptides (millions or more) that do not possess this consensus to determine whether one or more new sequences can accomplish the same binding interactions and whether a new consensus sequence' will be developed. Another extension of these methods is molecular recognition processes involving nonpeptides, such as sugars, polysaccharides, nucleotides, and lipids. Again, some very critical issues can be addressed. Many other possibilities exist for exploiting molecular diversity, and acceleration can be expected in the development of assay methods, chemical methods, and physical methods to examine complex diverse mixtures. In this regard, it is likely that the development of new synthetic methods to prepare large, diverse chemical structures will challenge the current methods of structural elucidation.

Original languageEnglish (US)
Pages (from-to)75-83
Number of pages9
JournalNIDA Research Monograph Series
Issue number134
StatePublished - Dec 1 1993

ASJC Scopus subject areas

  • Medicine (miscellaneous)

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