Peptoid libraries

Drug Discovery via Smaii-Moiecuie Peptoid Libraries... 

Drug Discovery via Small-Molecule Peptoid Libraries I 7... 

W. H. Discovery of nanomolar ligands for 7-transmembrane G-protein-coupled receptors from a diverse N-(substi-tuted)glycine peptoid library. J. Med. Chem. 1994, 37, 2678-2685. 

S., Beglinger, C., and Eberle, A.N. A combinatorial peptoid library for the identification of novel MSH and GRP/ Bombesin receptor ligands. J. Receptor Signal Transduct. Res. 1999, 19, 449-466. 

The design of a peptoid library using non-peptoid leads such as met-enkephalin and morphine represents an important practical instance of a rational... 

Nonoligomeric libraries. Peptide and peptoid libraries are examples of oligomeric (polymeric) libraries made up of repeating monomers (a-amino acids, A-substitutcd glycines). Random libraries composed of nonoligomeric compounds have been extensively explored. One illustration comes from the former laboratories at Organon (Fig. 1.6) (16). Thirteen different secondary amino-phenol inputs were attached to solid support by reaction with REM resin yielding resin-bound b-amino propionates. Two-site derivatization was then used to drive library diversity. The free phenolic OH was subjected to O-alkylation,... 

The submonomer method has two distinct advantages over the premade monomer method (1) the formation of the monomer on the resin eliminates the need for -protection (2) this method simplifies the synthesis of peptoid libraries, especially those that contain nonfunctionalized N-alkylated side chains, by using commercially available amines. Moreover, the diversity of these libraries is huge. 

Scheme 1. Multipin SPOC synthesis of peptoid libraries.

FIGURE 9.20 Fluoroaryls tags application to a peptoid library. 

The compound selection methods described thus far can be used to select compounds for screening from an in-house collection, or to select which compounds to purchase from an external supplier. In combinatorial library design, however, it is necessary to select subsets of reactants for actual synthesis. The two main strategies for combinatorial library design are reactant-based selection and product-based selection. In reactant-based selection, optimized subsets of reactants are selected without consideration of the products that will result and any of the compound selection methods already identified can be used. An early example of reactant-based design is that already described by Martin and colleagues which is based on experimental design and where diverse subsets of reactants were selected for the synthesis of peptoid libraries [1]. 

Peptidomimetic ligands for opioid receptors have also been identified from combinatorial libraries. Screening of an N-(substi-tuted)glycine peptoid library for affinity for ix opioid receptors yielded novel structures (251) with high affinity for these receptors (K = 6-46 nM) (953). A library of dipeptide amides with alkyl substituents on both the interior and C-terminal amides were prepared, and high affinity agonists for all three opioid receptors identified from the library (see Ref 946). Peptide libraries can also be further modified ["libraries from libraries" (954)] to yield new potential ligands for receptors. Thus an acety-... 

The mass encoding strategy was used by Wagner and co-workers [33] for the synthesis of a peptoid library. A set of 20 14N 15N ratio-encoded imidazoles was synthesized to investigate pharmacokinetic applications of isotopic labeling . 

The access to peptoids was simplified with the solid-phase submonomer approach (Scheme 21) reported by Zuckerman et al. [56]. As shown in Scheme 21, the first step consists of acylation of the resin-bound amine with bromoacetic acid and DIC as the coupling agent, and in a second step, the side chain is introduced by nucleophilic substitution of the halide with an excess of a primary amine. This method, which allows the preparation of a wide variety of oligomers, has been applied successfully to the generation of diverse combinatorial peptoid libraries [50]. Furthermore, A-hlkyl glycine residues containing peptide or peptoid-peptide hybrids can be read-... 

Berkessel et al. took a diversity-based approach to the discovery of functional models for GOase 42). Based on the known coordination pattern of the catalytically active copper ion (X-ray crystal structure of GOase from Dactylium dendroides, schematically in Scheme 12), the peptide/peptoid library 29 (Scheme 13) was designed. In this library, the Gly-D-Pro-turn positions the four amino acids X -X such that they can coordinate a copper ion. The four positions X X were occupied, in a combinatorial manner, by either histidine, tyrosine, the Cys22s-Tyr272-model mod-Cys (30), and in particular the TEMPO-derived amino acid TOAC (31) (Scheme 13). Thus, the TOAC-derived library comprised a total of 81 decapeptides, and it was synthesized... 

Martin and co-workers counted the total number of substructural fragments up to seven bonds long found in entire libraries as an estimate of chemical functional group diversity. They showed that although synthetic oligomeric combinatorial peptoid libraries were far more diverse than combinatorial biopolymer libraries, they still contained only about as many substructures as just the 45 top selling small molecule drugs. 

G. M. Figliozzi, D. A. Goff, M. A. Siani, R. J. Simson, S. C. Banville, E. G. Brown, L. Wang, L. S. Richter, and W. H. Moos, J. Med. Chem., 37, 2678 (1994). Discovery of Nanomolar Ligands for 7-Transmembrane G-Protein-Coupled Receptors from a Diverse N-(Substi-tuted)Glycine Peptoid Library. 

In 2008, Chongsiriwatana et al published a follow-up study on the previously reported antimicrobial peptoids. A second-generation peptoid library was designed, again, to mimic the amphipathic stmcture of magainin-2, this time... 

M. Abbas, J. Betbke, L. A. Wessjohann, Chem. Commun. 2006, 541-543. One pot synthesis of selenocysteine containing peptoid libraries by Ugi multicomponent reactions in water. 

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