Combinatorial Libraries

 Few fields have emerged as rapidly as the technologies collectively referred to as combinatorial chemistry. The origins of combinatorial “thinking” as applied to biological problems can be traced to our understanding of the immune system. Humoral immunity is based on the generation of billions of different antibody molecules through unique gene recombination events. Upon exposure to a foreign immunogen, the subset of the antibody repertoire with specificity for the invader is clonally expanded. During expansion, the active antibody subpool undergoes additional recombination and mutation events, and the most active variants are further selected. This process is reiterated until mature antibody molecules are produced that are highly optimized against the foreign antigen. In essence, antibody repertoires are combinatorial libraries—collections of related but distinct molecules representing different combinations of genetic elements. The recognition of these facts preceded the creation of the first combinatorial library, which was based upon the synthesis and screening of large numbers of synthetic peptides in order to identify selected antigenic determinants of a viral pathogen (1). Given the parallels between the immune system and combinatorial libraries, it is not surprising that the original application of this emerging technology was in the derivation of immunogens capable of stimulating immune protection in animals not yet exposed to certain pathogens.

The hallmarks of a combinatorial approach are the generation and use of complex compound mixtures to identify molecules with desirable properties. Four basic operations underpin combinatorial approaches: (i) generation of libraries containing related but diverse compounds, (ii( selection of molecules with desirable properties from the library, (iii) characterization of the selected molecules, and (iv) amplification of the identified products. Depending upon the chemical composition of the library, the selected molecules may require amplification before structure determination. For example, DNA libraries can be amplified using the polymerase chain reaction ) PCR) before the final products are identified by sequencing. Synthetic peptides and small molecules cannot be amplified per se and must be subjected to structural elucidation, and then resynthesized for subsequent use. Regardless of the library composition, the four operations enumerated above can be applied in an iterative fashion to progressively refine the selected compounds.

 Several entries in this volume deal with the application of combinatorial approaches to complex biological problems. Issues central to the implementation of combinatorial technologies in biological systems will be described below, including cognitive aspects of library design, practical aspects of library construction, basic issues in affinity selection and library screening, and discussions of different library types and their applications. The breadth of the topic Combinatorial Libraries is so expansive that it is impossible to cover any topic in great detail. The entries entitled Libraries, Combinatorial Synthesis, and Affinity Selection are intended to provide a generic introduction to the principles underlying combinatorial operations. The remaining entries, DNA libraries, Genomic libraries, cDNA libraries, Expression libraries, Peptide libraries, and Phage display libraries, provide more specific details regarding the major types of combinatorial libraries in widespread use. Small molecule synthesis or drug discovery applications are not dealt with in detail, although many basic concepts from these fields are presented. The reader is referred to the suggested reading list for additional discussion of these related topics.  

References

1. H. M. Geysen, R. H. Meleon, and S. J. Barteling (1984) Proc. Natl. Acad. Sci. USA 81, 3998–4002.

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Other Attenuated Systems: Operons, Bacillus subtilis and HIV

Coupling Translation to Termination

trp Multiple Secondary Structures in trp Leader RNA

Early Explorations of the Hypersynthesis

The Serendipitous Discovery of trp Enzyme Hypersynthesis

Rapid Induction Capabilities of the trp Operon

The Aromatic Amino Acid Synthetic Pathway and its Regulation

How AraC Protein Loops and Unloops

DNA Looping and Repression of araBAD

Binding Sites of the ara Regulatory Proteins

Endoplasmic Reticulum-Associated Degradation and the Unfolded Protein Response

Protein Folding and Modifications in the Endoplasmic Reticulum