Synthesis and structure–activity relationship studies of peptidomimetic PKB/Akt inhibitors: The significance of backbone interactions

Tal‐Gan, Yftah; Freeman, Noam S.; Klein, Shoshana; Levitzki, Alexander; Gilon, Chaim

doi:10.1016/j.bmc.2010.02.031

Cited by 24 publications

(34 citation statements)

References 44 publications

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“…N-modified amino acids are known to impart unique properties to peptides, including distinctive conformational propensities to the peptide backbone, increased cellular permeability, and resistance to protease mediated degradation (9)(10)(11)(12)(13). The generation of an orthogonal suppressor prolyl-tRNA (tRNA Pro )/prolyl-tRNA synthase (ProRS) pair may facilitate the site-specific incorporation of UAAs with backbone modifications into proteins, which has been difficult to achieve using existing tRNA/aaRS pairs.…”

mentioning

confidence: 99%

Evolution of multiple, mutually orthogonal prolyl-tRNA synthetase/tRNA pairs for unnatural amino acid mutagenesis in Escherichia coli

Chatterjee

Xiao

Schultz

2012

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

102

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The site-specific incorporation of unnatural amino acids (UAAs) into proteins in living cells relies on an engineered tRNA/aminoacyl-tRNA synthetase (tRNA/aaRS) pair, orthogonal to the host cell, to deliver the UAA of choice in response to a unique nonsense or frameshift codon. Here we report the generation of mutually orthogonal prolyl-tRNA/prolyl-tRNA synthase (ProRS) pairs derived from an archaebacterial ancestor for use in Escherichia coli . By reprogramming the anticodon-binding pocket of Pyrococcus horikoshii ProRS (PhProRS), we were able to identify synthetase variants that recognize engineered Archaeoglobus fulgidus prolyl-tRNAs (Af-tRNA Pro ) with three different anticodons: CUA, AGGG, and CUAG. Several of these evolved PhProRSs show specificity toward a particular anticodon variant of Af-tRNA Pro , whereas others are promiscuous. Further evolution of the Af-tRNA Pro led to a variant exhibiting significantly improved amber suppression efficiency. Availability of a prolyl-tRNA/aaRS pair should enable site-specific incorporation of proline analogs and other N-modified UAAs into proteins in E. coli . The evolution of mutually orthogonal prolyl-tRNA/ProRS pairs demonstrates the plasticity of the tRNA–aaRS interface and should facilitate the incorporation of multiple, distinct UAAs into proteins.

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confidence: 99%

Evolution of multiple, mutually orthogonal prolyl-tRNA synthetase/tRNA pairs for unnatural amino acid mutagenesis in Escherichia coli

Chatterjee

Xiao

Schultz

2012

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

102

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“…N‐MeArg1 and N‐MeHol7 were completely degraded within 30 min, compared to the parent PTR6154 that was completely degraded only after 120 min (Figure 2), suggesting that the methylation of these residues results in peptide conformations with higher affinities for the protease binding site. N‐MeAla2, in which proline was replaced by N ‐methyl alanine (50), was less resistant to degradation than PTR6154 (Figure 2). This result can be accounted for by the conformational freedom gained by the replacement of the rigid proline residue with the less rigid N ‐methyl alanine residue, resulting in an extended peptide backbone conformation that is more accessible to peptidase binding.…”

Section: Resultsmentioning

confidence: 99%

“…(52). Our peptidomimetic structure‐activity relationship studies included N ‐methyl peptides, peptoids, backbone cyclic peptides, and aza‐peptides (50,53,54). Because the parent peptide, PTR6154, contains both Arg and Tyr residues, it is a good model for a Trypsin/Chymotrypsin stability assay.…”

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confidence: 99%

“…Recently, we reported an extensive structure-activity relationship study of the protein kinase B (PKB ⁄ Akt) peptide inhibitor, PTR6154 (Arg-Pro-Arg-Nva-Tyr-Dap-Hol) introduced by Litman et al (52). Our peptidomimetic structure-activity relationship studies included Nmethyl peptides, peptoids, backbone cyclic peptides, and aza-peptides (50,53,54). Because the parent peptide, PTR6154, contains both Arg and Tyr residues, it is a good model for a Trypsin ⁄ Chymotrypsin stability assay.…”

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confidence: 99%

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Metabolic Stability of Peptidomimetics: N‐Methyl and Aza Heptapeptide Analogs of a PKB/Akt Inhibitor

et al. 2011

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Linear peptides suffer from poor pharmacokinetic and pharmacodynamic properties. Peptidomimetics are designed to overcome these pharmacological drawbacks while maintaining the biological effects of the parent peptides. Aza-peptides, in which an alpha carbon is replaced with nitrogen, are promising peptidomimetic analogs; however, little is known about the stability of these analogs toward enzymatic degradation. We performed systematic aza and N-methyl scans of a PKB/Akt inhibitor, PTR6154. We evaluated the stability of the aza-scan and N-methyl scan libraries toward enzymatic degradation by trypsin/chymotrypsin. Our results indicate that the modification site is important for metabolic stability and that aza-peptides have a more global effect than N-methylation, affecting cleavage sites distant from the modification site.

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“…There is precedent for this approach in that peptoids can have specific protein binding activity. Their interactions with proteins can be optimized by rational chemical design and have been used as functional ligands for molecules such as VEGF receptor 2, an antigen-specific T cell receptor, and PKB/Akt (Udugamasooriya et al, 2008; Gocke et al, 2009; Tal-Gan et al, 2010). We have used un-biased peptoid libraries to identify antibodies that can characterize patients with SLE without regard to the antigenic specificity of the antibody.…”

Section: Introductionmentioning

confidence: 99%

Discovery of biomarkers for systemic lupus erythematosus using a library of synthetic autoantigen surrogates

Quan

Lakhanpal

Reddy

et al. 2014

Journal of Immunological Methods

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Antibodies to a wide range of self-antigens, including those directed against nucleic acids or nucleic acid-binding proteins are the essential biomarkers for diseases such as systemic lupus erythematosus (SLE). Highly complex libraries of nonamers consisting of N-substituted glycines (peptoids) were screened for compounds that bound IgG from patients with SLE and earlier, incomplete autoimmune syndromes. Peptoids were identified that could identify subjects with SLE and related syndromes with a high sensitivity (70%) and specificity (97.5%). Immobilized peptoids were used to isolate IgG from both healthy subjects and SLE patients that reacted with known RNA-binding proteins. In the case of SLE patients, the peptoid-purified IgG reacted with several autoantigens, suggesting that the peptoids are capable of interacting with multiple, structurally similar molecules. These results show that the measurement of IgG binding to peptoids can identify subjects with high levels of pathogenic autoantibodies.

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Synthesis and structure–activity relationship studies of peptidomimetic PKB/Akt inhibitors: The significance of backbone interactions

Cited by 24 publications

References 44 publications

Evolution of multiple, mutually orthogonal prolyl-tRNA synthetase/tRNA pairs for unnatural amino acid mutagenesis in Escherichia coli

Evolution of multiple, mutually orthogonal prolyl-tRNA synthetase/tRNA pairs for unnatural amino acid mutagenesis in Escherichia coli

Metabolic Stability of Peptidomimetics: N‐Methyl and Aza Heptapeptide Analogs of a PKB/Akt Inhibitor

Discovery of biomarkers for systemic lupus erythematosus using a library of synthetic autoantigen surrogates

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