Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1995-02-21
1998-09-29
Green, Lora M.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 23, 435 681, 436501, 436518, 530338, 530343, G01N 3353
Patent
active
058144609
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to novel methods for generating and screening peptides which are useful for a variety of applications.
2. Description of the Background Art
Small peptides (2-15 amino acids) are capable of possessing unique spatial and thermodynamic properties which allow them to bind specifically to particular proteins. The binding of these peptides to such proteins can transiently or permanently eliminate or activate the function of those proteins. Thus a peptide which binds to, and eliminates the function of a coat protein of a virus could serve as an effective pharmacologic agent against that virus. Similarly, a peptide which binds to and activates a receptor for taste or olfaction could serve as a useful active agent for flavoring or perfumes. There is considerable interest in the pharmaceutical industry in the development of such useful peptides. The major difficulty is that the production and screening of individual peptides is inefficient and labor intensive. Peptides must be made individually and tested for their ability to bind the protein of interest. Because of the difficulty of making and screening each individual peptide, it is not possible to screen large numbers of peptides. There is, therefore, a need for methods which allow for rapid and efficient screening of a large number of peptides. An ideal system would provide for the simultaneous synthesis and screening of every possible peptide of a particular size.
A variety of proteolytic enzymes, including trypsin, chymotrypsin, pepsin, papain, bromelain, thermolysin and S. griseus proteinase, hydrolyze peptide bonds. The rate of hydrolysis is influenced by temperature, substrate and enzyme concentration, enzyme specificity, and substrate sequence. S. griseus proteinase, papain, and the subtilisin enzymes are known to have broad substrate specificity, but for total enzymatic hydrolysis, the use of a mixture of enzymes is preferred. Hill, "Hydrolysis of Proteins", in Advances in Protein Chemistry, 20: 37, 89-90 (Anfinsen, Jr , et al., eds., 1965).
In 1937, it was demonstrated that a proteolytic reaction could be reversed. Soon thereafter, proteases were used for both stepwise and fragment condensation synthesis of peptides of predetermined sequence. Since the enzymes differed in terms of which peptide bonds would be formed, several different enzymes had to be used in succession to make oligopeptides. Unfortunately, enzymatic chain elongation could endanger preexisting bonds. See Sakina, et al., Int. J. Peptide Protein Res., 31: 245-52 (1988); Kullman, Proc. Nat. Acad. Sci. (U.S.A.) 79: 2840-44 (1982).
One problem in enzymatic synthesis of peptides is that hydrolysis is thermodynamically favored under normal conditions. Thus, the equilibrium must be shifted. Homandberg, et al., Biochemistry, 21: 3385-8 (1982) teaches that one may use a "molecular trap", that is, a molecule which has an affinity for a particular peptide of known amino acid sequence, to shift the equilibrium to favor the synthesis of such a peptide.
Varied approaches have been utilized for the purpose of generating diverse populations of peptides.
"Semisynthetic" peptides and proteins have been prepared by (1) limited proteolysis of naturally occurring polypeptides to yield a workable set of fragments, (2) chemical synthesis of an additional oligopeptide, and (3) reconstruction of synthetic and native partners. The technique is typically used to prepare analogues of naturally occurring polypeptides. Chaiken, CRC Critical Reviews in Biochemistry, 255 (September 1981). Ruggeri, et al., P.N.A.S. (U.S.A.), 83: 5708-12 (August 1986) prepared a series of synthetic peptides in lengths up to 16 residues that were modeled on various platelet-binding peptides. The technique used was one of solid state synthesis by chemical means, but using individual compartmentalized peptide resins to impart the desired variety. See Houghten, et al., P.N.A.S. (U.S.A.), 82: 5131-35 (1985). Yet another approach to generating a variety of peptides is
REFERENCES:
patent: 5366862 (1994-11-01), Venton et al.
Hopfinger Anton J.
Lebreton Guy
Venton Duane L.
Cooper Iver P.
Diatide, Inc.
Green Lora M.
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