Peptide library approach

Obita, T., Muto, T., Endo, T. and Kohda, D. (2003). Peptide library approach with a disulfide tether to refine the Tom20 recognition motif in mitochondrial presequences. J. Mol. Biol. 328, 495-504. 

A prerequisite for CTL-mediated immune response is the formation of the MHC-class I-peptide complex and subsequent recognition by the T-cell repertoire, which can be analyzed in cell lysis assays with MCr-loaded target cells. Chromium release is a measure for peptide-induced cell lysis by CTL, and indicates the potency of the peptide to serve as an allele-specific epitope. A synthetic epitope has been identified with the peptide library approach to elucidate the molecular basis for the observed cross-recognition of two ligands by a single receptor [53]. 

In order to avoid translational invariance when studying peptide binding to class II molecules with peptide libraries, two approaches would be possible. First, the incorporation of more than one defined residue in the undecapeptide library, e.g., a common hydro-phobic residue in the first anchor position of DR-ligands, would prevent translational invariance. However, universal applicability of the peptide library approach would be lost,... 

Samson, I., Kerremans, L., Rozenski, J., Samyn, B., Van Beeumen, J., Van Aerschot A. and Herdewijn, R, Identification of a peptide inhibitor against glycosomal phospho-glycerate kinase of Trypanosoma brucei by a synthetic peptide library approach, Bioorg. Med. Chem. Lett., 3 (1995) 257-265. 

SI Cho, W Zheng, A Tropsha. Rational combinatorial library design 2. Rational design of targeted combinatorial peptide libraries using chemical similarity probe and the inverse QSAR approaches. J Chem Inf Comput Sci 38 259-268, 1998. 

Combinatorial chemistry has been used with great success to create libraries in the development of inhibitors in the field of peptide and nucleic acid recognition.5,6 The basic strategy of a library approach is to synthesize large sets of molecules at a time, even as complex mixtures, and then determine whether any of the compounds is inhibitory. The active compound must be subsequently identified. This strategy stands in contrast to the extremely laborious and expensive process of traditional medicinal chemistry, where individual molecules are carefully synthesized and evaluated. The... 

A library containing several million beads can be screened in a single afternoon. Furthermore, the library is reusable, as it may be washed in 8 M guanidine hydrochloride and then re-screened using a different probe. This split synthesis approach displays the ability to generate peptide libraries of incredible variety, variety that can be further expanded by incorporation of, for example, D-amino acids or rarely occurring amino acids. 

In addition to sequential and chemical diversity, cyclic peptide libraries offer the possibility of conformational diversity where all components of the library differ from each other in their conformation, despite the identical connectivity. In this context two complementary approaches have been proposed, i.e. spatial screening based on head-to-tail cyclic peptides and cycloscan where the rest of the modes of cyclization are exploited. 

For the cycloscan, conformational libraries are synthesized by cyclization of continuous or noncontinuous bioactive epitopes and not by their insertion into a scaffold. Originally, the concept of cycloscan was introduced for the generation of backbone-cyclized peptide libraries 467 however, cycloscan can also be applied to other modes of cyclization. In this approach all components of each sublibrary bear the identical sequence, and differ from each other in distinct parameters that affect their conformation, but do not alter their connectivity, and hence their potential bioactivity. This is achieved by gradually introducing discrete conformational perturbations, which allow an efficient screening of the conformational space of the parent peptide. The majority of the components of such libraries should be inactive, because they do not overlap the bioactive conformation. However, the peptide that does fit the bioactive conformation should be very potent and have all the pharmacological advantages of cyclic peptides. 

Beyond these design methods, some combinatorial approaches have been developed on the purpose of ligand selection. S3mthetic peptide libraries which include all sequences for a length of a protein structure are one of these approaches. By means of these libraries, in vitro prediction of the action of the library mixture as it passes through the surface where the protein of concern is immobilized is possible. The ligands which possess affinity to the immobilized protein are... 

Solid-phase peptide synthesis has become widely used for the preparation of peptides built from a-amino acids of varying sizes and complexity, and also in the recent synthetic approaches to peptide libraries. It has been recognized that the use of solid-phase protocols for the synthesis of (3-peptides is likely to make them more attractive lead compounds in drug discovery. Although still at an early stage, work has begun to develop suitable protocols for automated (3-peptide synthesis. 

The use of peptide libraries to study T cell specificity was first demonstrated by Gundlach et al.45 Since then studies have focused on T cell specificity with emphasis on the identification of immunodominant epitopes in infectious diseases and autoimmune disorders, and on the determination of tumor antigens. The PS-SCL approach, as described above, was successfully used to study T cell recognition and to identify and optimize peptides having a range of activities in stimulating proliferative responses, cytokine production, and/or lysis by CD4+ and CD8+ murine and human T cell clones and T cell lines of known and unknown specificity.46-53... 

Miller et al. achieved selective functionalization of the enantiotopic hydroxyl groups of meso-inositols. In particular, they were able to convert myo-inositol 49 to either mono-phosphorylated D-myo-inositol-l-phosphate 50 or D-myo-inositol-3-phosphate mt-50 in high yield and with excellent ee (98%) (Scheme 13.25) [40, 41], This remarkable result was achieved by using the pentapeptides 51 or 52 as catalyst. These catalysts were identified from peptide libraries by a combinatorial approach. The peptides 51 and 52 are highly selective and complementary low-molecular-weight kinase mimics. It is also interesting to note that the opposite enantioselectivity of catalysts 51 and 52 could hardly have been predicted on the basis of the type and sequence of the amino acids involved. (Application of the Miller peptide catalysts to the kinetic resolution of racemic alcohols is discussed in Section 12.1.)... 

Combinatorial approaches in synthetic chemistry allow the high-throughput screening of millions of compounds. It is the aim to establish such approaches in biosynthetic systems by creating module assemblies, which provide a new tool to create peptide libraries. The large number of different modules in peptide synthetase systems is suitable for creating a pool of many different enzymes in order to detect a useful compound in the near future [2,51],... 

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