Synthetic libraries

The reason for the lack of lead compounds from synthetic libraries in some therapeutic areas such as anti-infectives, immunosuppression, oncology, and metabolic diseases may be due to the different chemical space occupied by natural products and synthetic compounds. 

Several other protected diamino acids involve aromatic rings (Fig. 3).23-27 Their structures may also be suitable as scaffolds for building synthetic libraries, but this application has been proposed only for compounds 12, 15, and 16 24,25 Whereas most of the structures displayed in Fig. 2 require stereoselective syntheses, the preparation of diamino acids 12-17 is facilitated by the absence of an asymmetric center. 

In ribosome display, the physical link between genotype and phenotype is accomplished by mRNA-ribosome—protein complexes, which are directly used for selection. If a library of different mRNA molecules is translated, a protein library results in which each protein is produced from its own mRNA and remains connected to it. Since these complexes of the proteins and their encoding mRNAs are stable for several days under the appropriate conditions, very stringent selections can be performed. As all steps of ribosome display are carried out in vitro, reaction conditions of the individual steps can be tailored to the requirements of the protein species investigated, as well as the objectives of the selection or evolution experiment. Application of ribosome display has produced scFv fragments of antibodies with affinities in the picomolar range from libraries prepared from immunized mice (Hanes et al., 1998) and more recently from a naive, completely synthetic library (Hanes et al., 2000), and has been used to evolve improved off-rates and stability (Jermutus et al., 2000). 

Felder ER, Heizmann G, Matthews IT, Rink H, Spieser E, A new combination of protecting groups and links for encoded synthetic libraries suited for consecutive tests on the solid phase and in solution, Mol. Diversity, 1 109-112, 1995. 

Synthetic compounds accumulated through decades by large corporations represent a source of chemical diversity. A synthetic library has the advantage of consisting of pure compounds with known physicochemical properties. Furthermore, the concentration of the compounds can be adjusted, and a defined synthetic scheme is usually available for future scale-up. The big disadvantage of these libraries is that they are biased the compounds have been synthesized in the past for specific projects and are thus non-random. This often results in limited chemical diversity and low affinity for the target. In addition, hits identified in these libraries may not be patentable because of previous disclosure of their structure. 

Synthetic library Naive library Antigen-biased library... 

Academic institutions are assembling both synthetic libraries and natural product repositories. The National Cancer Institute (NCI) operates a well-received resource providing natural product extracts, mostly from marine sources (http //www.dtp.nci.nih.gov/branches/npb/repository.html). 

Synthetic Libraries Beyond Conventional Pathway Engineering. 121... 

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