Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-12-18
1998-11-10
Green, Lora M.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 71, 436501, 436518, 436528, 436531, 436533, 436173, G01N 3353, C12Q 168
Patent
active
058341951
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a method for the identification and analysis of members of combinatorial libraries, wherein the identified member has a demonstrated pharmacological or physiological activity.
BACKGROUND OF THE INVENTION
Over the past ten years, there has been a growing demand for the production and identification of small molecules that have pharmacological activity as, for example, agonists or antagonists of various cellular acceptor molecules, such as cell-surface receptors, enzymes, or antibodies. Such small molecules can be peptides, oligonucleotides, or other organic compounds, such as heterocyclics and the like. The unifying feature of these small molecules is operational in that they bind specifically to known acceptors. In consequence of such binding, a physiological response occurs whereby certain biological processes are modulated, which can have applications in medicine and agriculture.
Searching for small molecules that are useful as pharmaceuticals entails (1) generating collections of such molecules, (2) screening such molecules for physiological activity, and (3) identifying the structure of molecules that provide a positive result in the screen. The first two steps can be accomplished using methods well-known in the art, some of which are described herein for purposes of clarity. The third step, where one determines the structure of a positively screened small molecule, has proven to be the time-limiting step in the overall process to discover new small molecule pharmaceuticals. This step is necessary to eliminate false positives or duplicates, and, of most importance, to produce the selected small molecule for a prospective pharmaceutical formulation.
Searching for such small molecules has involved screening collections of natural materials, such as fermentation products, plant or animal tissue extracts, or libraries of synthesized molecules. Chemical assays have been designed that merely identify those species that bind a particular acceptor molecule or, in a bioassay, assess the ability of tested molecules to effect certain physiological reactions. Screening of such collections often, at most, provides leads that must be refined by more stringent techniques and expanded testing of related molecules. All of these techniques are limited severely by the available concentration of any particular small molecule and the resolving power of the screening and analysis techniques. As a result, the process of production and identification of small molecules that have pharmacological activity, a process termed "irrational drug design" by Brenner and Lerner (Proc. Natl. Acad. Sci. USA, 89, 5381-5383 (1992)), "requires continual improvement methods of selection." Id. at page 5381.
A repertoire of small molecules, wherein each molecule thereof can be represented preferably in at least femtomole quantities, typically is produced by what are termed multiple methods of synthesis or parallel chemical synthetic protocols. Such repertoires are commonly referred to as "combinatorial libraries," for reasons that will become plain below. With reference to peptides, such synthetic methods have been disclosed by Jung and Beck-Sickinger (Angew. Chem. Int. Ed. Engl., 31, 367-383 (1992)). Methods for the production of heterocyclic libraries (see Bunin and Ellman, J. Am. Chem. Soc., 114, 10997-10998 (1992)) and nucleic acid libraries (referred to in Brenner and Lerner, supra) have also been published. Other methods for the construction of combinatorial libraries include those of Kerr et al., J. Am. Chem. Soc., 115, 2529 (1993); Lam et al., Nature, 354, 82 (1991); Houghten et al., Nature, 354, 84 (1991); and Fodor et al., Science, 251, 767-773 (1991) (see, also U.S. Pat. No. 5,143,854 (1992)).
In the methods cited above, members of a library are constructed from the coupling of chemical building blocks, such as amino acids, nucleic acids, or variant organic monomers and side groups. Resultant libraries consist of different individual species, the potential number (k) of whic
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Benkovic Stephen J.
Brummel Christopher L.
Lee Irene N. W.
Winograd Nicholas
Green Lora M.
Monahan Thomas J.
The Penn State Research Foundation
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