Nonpeptide Libraries Research Articles

Synthesis of a Scaffold for the Creation of Non-Peptide Libraries

5β-Cholanic acid derivative XVII was prepared as a skeleton for the creation of non-peptide libraries. In positions 3, 7 and 12, different functional groups were designed in order to provide for the attachment of various building blocks linked to them.

Use of Large Combinatorial Chemical Libraries for Anticancer Drug Discovery

AbstractA new technology for drug discovery (Selectide technology) has been developed which greatly extends the capability for rapid molecular and cellular screening to large libraries containing millions of chemically synthesized compounds. Using a split synthesis approach to condensation chemistry, we recognized that each individual compound of potential interest is located on a different solid phase resin bead. Screening for binding activity on the bead surface: In order to screen for biological activity, we used several cleavable linkers which could release a portion of the compound from each bead into the solution phase in each of two sequential steps. For libraries comprised of peptides, there is sufficient residual peptide on each bead to permit sequence determination via Edman degradation. For non-peptide libraries, a system of peptide encoding is used on each bead so that the structure of the non-peptide compound can be determined by decoding the information conveyed by the peptide (which can be ...

One-bead-one-structure combinatorial libraries.

Combinatorial libraries employing the one-bead-one-compound technique are reviewed. Two distinguishing features characterize this technique. First, each compound is identified with a unique solid support, enabling facile segregation of active compounds. Second, the identity of a compound on a positively reacting bead is elucidated only after its biological relevance is established. Direct methods of structure identification (Edman degradation and mass spectroscopy) as well as indirect "coding" methods facilitating the synthesis and screening of nonpeptide libraries are discussed. Nonpeptide and "scaffold" libraries, together with a new approach for the discovery of a peptide binding motif using a "library of libraries," are also discussed. In addition, the ability to use combinatorial libraries to optimize initially discovered leads is illustrated with examples using peptide libraries.

Selectide Technology: Bead-Binding Screening

The Selectide process is a random synthetic chemical library method based on the one-bead one-peptide (structure) concept. A "split-synthesis" method is used to generate huge random libraries (10 6-10 8). At the end of the synthesis, each bead expresses only one chemical entity (e.g., peptide). The whole library is then tested simultaneously for binding to a specific acceptor molecule of biologic interest. The ligand bead that interacts specifically with the acceptor molecule is then isolated for structure determination. Once a binding motif is identified, a secondary library (based on the motif of the primary screen) is generated and screened under a more stringent condition to identify leads of higher affinity. This process can be applied to both peptide and nonpeptide (small organic) libraries. In the case of nonsequencable structure libraries, the coding principle has to be applied for structure elucidation of positively reacting beads. Coding peptide is synthesized in parallel to the screening structure, and classical Edman degradation (one or multiple-step) is used for structural analysis. To exclude the possibility of interaction of the macromolecular target (e.g., receptor, enzyme, antibody) with the coding structure, a synthetic technique for segregation of the surface (screening structure) and the interior (coding structure) of the beads was developed. The one-bead one-structure process is invaluable in drug discovery for lead identification as well as further optimization of the initial leads. It also serves as an important research tool for molecular recognition.