Representations of bimolecular interactions

Details Representations of bimolecular interactions Representations of bimolecular interactions

1999-05-06

2000-12-26

Jones, W. Gary

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

435 5, 435 711, 5303883, C12Q 170, C12Q 168, C12P 2100, C12P 2108

Patent

active

061657220

DESCRIPTION:

BRIEF SUMMARY
FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to representations of bimolecular interactions and, more particularly, to the exploitation of these interactions for the production of new pharmaceuticals, such as vaccines, and diagnostic or research assays, such as antibody-based assays.
Bimolecular interactions are important for a variety of biological processes, including pathological processes. Such interactions typically involve the recognition of a three-dimensional structure, such as a protein, carbohydrate or drug ligand, by another such structure. Each of these structures is an example of a biological unit, so that such bimolecular interactions can be more generally described as an interaction between two biological units. Nature performs with ease many such interactions, which so far have proven largely refractory to analysis. Such difficulty has had a negative impact on the fields of vaccine and drug development in particular, which have had to rely on a trial-and-error approach, in the absence of defined rules for the production of novel vaccines and other pharmaceuticals. However, such trialand-error approaches are costly and inefficient. Clearly, new approaches are needed in these fields.
The problem of vaccine and drug development, which is associated with bimolecular interactions, can be narrowed to the interaction between specific epitopes on the two molecules involved. In the case of two proteins, these epitopes can be composed of particular peptides, or of peptides and carbohydrates. For a drug and its receptor, these epitopes may consist of peptides on the receptor, and functional groups on the drug. These different materials would appear to indicate that these different types of bimolecular interactions would require different systems for study. However, as described below, all of these different epitopes can be mimicked by peptides. Thus, a single system for screening large numbers of peptides could be employed to explore all of these different types of epitope interactions, since all of these interactions could be represented by different types of peptide libraries. For example, mimotopes of a carbohydrate could be found using a random peptide library, which contains all possible peptides of a given length. Alternatively, an antigen library could be used to represent peptides derived from the primary sequence of an antigen, such as a protein, for example. If such an antigen library represented all possible peptides of a given length contained within the protein, the library could be said to represent a complete pepscan of the antigen.
Such a complete pepscan could be found in a reference by Baughn et al. [Baughn, R. E., Demecs, M., Taber, L. H. and D. M. Musher, Infection and Immunity, 1996, 64:2457-2466] for the 15-kDa lipoprotein of Treponema pallidum, which causes syphilis. Overlapping decapeptides (ten amino acids) were synthesized, each of which overlapped the next by nine amino acids, and were offset by one amino acid, so that a complete set of decapeptides was obtained. These were then screened with sera from syphilitic rabbits in an ELISA (enzyme-linked immunosorbent assay), to find those peptides which reacted with antibodies against syphilis. The limitations to such an approach are immediately obvious, particularly since the synthesis of such a large number of peptides is both tedious and difficult to manage. Clearly, producing complete pepscans by peptide synthesis limits the approach for small proteins. Indeed, Baughn et al. note that their choice of protein was strongly influenced by size.
Thus, a new approach to the exploration of bimolecular interactions, and by extension to the fields of vaccine and drug development, is required. This approach uses combinatorial phage display peptide libraries to quickly sort through a huge number of peptides to find those peptides of interest, by a screening assay which functionally selects for a particular behavior in a peptide, as described by G. P. Smith and J. K. Scott [Scott, J. K. and G. P. Smith, Science, 19

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Germino, et al. "Screening for in vivo protein-protein interactions" Pro.Natl.Acad.Sci, 90:933-937, 1993.

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