Speculations on the design of nonpeptidic peptidomimetics

Farmer, P. S.; Ariëns, E. J.

doi:10.1016/0165-6147(82)91184-1

Cited by 84 publications

(37 citation statements)

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“…We refer to these oligomers as "peptoids," in recognition of their conceptual lineage. They are also an example of compounds given this name previously by Farmer and Ariens (15) and Horwell (16). In this report, the rationale behind this selection is described, along with general routes to the synthesis of a variety of protected N-substituted glycines and their assembly into peptoid oligomers.…”

mentioning

confidence: 99%

Peptoids: a modular approach to drug discovery.

Simon¹,

Kania²,

Zuckermann³

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

923

644

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Peptoids, oligomers ofN-substituted glycines, are described as a motif for the generation ofchemically diverse libraries of novel molecules. Ramachandran-type plots were calculated and indicate a greater diversity of conformational states available for peptoids than for peptides. The monomers incorporate t-butyl-based side-chain and 9-fluorenylmethoxycarbonyl a-amine protection. The controlled oligomerization of the peptoid monomers was performed manually and robotically with in situ activation by either benzotriazol-lyloxytris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(pyrrolidino)phosphonium hexafluorophosphate. Other steps were identical to peptide synthesis using a-(9-fluorenylmethoxycarbonyl)amino acids. A total of 15 monomers and 10 oligomers (peptoids) are described. Preliminary data are presented on the stability of a representative oligopeptoid to enzymatic hydrolysis. Peptoid versions of peptide ligands of three biological systems (bovine pancreatic a-amylase, hepatitis A virus 3C proteinase, and human immunodeficiency virus transactivator-responsive element RNA) were found with affinities comparable to those of the corresponding peptides. The potential use of libraries of these compounds in receptor-or enzyme-based assays is discussed.Broad screening of compound libraries, of broths grown from soil samples, and of synthetic intermediates has been a fruitful method for discovery of lead compounds in pharmaceutical and agrochemical research (e.g., ref. 1). With the advent of automated chemical methods for solid-phase peptide and nucleotide synthesis, and of molecular biological methods for protein and nucleic acid synthesis, the stage has been set for the generation of new kinds of compound libraries, namely, collections of oligomeric biomolecules (2-14). Such libraries have been used to map epitopes for antibody binding, to discern ribonucleotide sequences with specific binding or catalytic activity, and to provide initial leads in receptor-based assays. Advantages of these oligomeric molecules are an almost limitless diversity as a result of their modular structure, the ease with which they can be synthesized and sequenced, and their inherent biological relevance. On the other hand, the metabolic instability of peptides and nucleotides and their poor absorption characteristics mean that any lead sequence will require extensive modification before in vivo activity can be expected.Many of these problems could be avoided if an alternative, modular system was devised, with a basis set of "unnatural" monomers and a method for their controlled oligomerization. A host of chemically and pharmaceutically interesting subunits or modules would generate a diverse and novel set of heteropolymers. Once an interesting compound has been identified from a library of such nonpeptide polymers, it can serve as a lead for drug discovery, further along the road to a metabolically stable drug. Optimized analogs of a lead compound could then be developed rapidly due to the modular synthetic nature of th...

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mentioning

confidence: 99%

Peptoids: a modular approach to drug discovery.

Simon¹,

Kania²,

Zuckermann³

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

923

644

View full text Add to dashboard Cite

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“…A major difficulty in these studies is the conformational flexibility of most peptides and the high dependence of their conformations on the surrounding environment which often leads to a conformational equilibrium. [6] The high flexibility of natural polypeptides is due to the multiple conformations that are energetically possible for each residue of the incorporated amino acids. Every amino acid has two degrees of conformational freedom, N-C α (Φ) and C α -CO (Ψ) resulting in approximately 9 (3 2 ) stable local conformations.…”

Section: Introductionmentioning

confidence: 99%

Peptidomimetics – A Versatile Route to Biologically Active Compounds

2009

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Proteins are vital for basically every known organism. Therefore the investigation of their structure, the development of a deeper understanding of protein-protein interactions and the design of novel peptides, which selectively interact with proteins are fields of active research. Small peptides consisting of the 20 natural amino acids typically show high conformational flexibility and a low in-vivo stability which hampers their application as tools in medicinal diagnostics or molecular biology. One very versatile strategy to overcome such drawbacks is the use of peptidomimetics. These are small

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“…The stereospecificity in the interaction can be counted for on basis of as few as three ligands, binding groups, in the molecule.1,2 This even holds true for the high selectivity in the interaction between antibody and antigen. The three hypervariable regions in the light chains of the antibody are the determinants here.3 The contributions to the binding energy obtained from the interaction of pairs of corresponding groups in the bioactive agent and receptor site show that participation of a triade of pairs can generate binding constants in the order of lop9 to lo-'' M. 2…”

Section: Introductionmentioning

confidence: 99%

Stereochemistry in the analysis of drug‐action. Part II

Ariëns

1987

Medicinal Research Reviews

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Speculations on the design of nonpeptidic peptidomimetics

Cited by 84 publications

References 5 publications

Peptoids: a modular approach to drug discovery.

Peptoids: a modular approach to drug discovery.

Peptidomimetics – A Versatile Route to Biologically Active Compounds

Stereochemistry in the analysis of drug‐action. Part II

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