- A solid-phase approach to mouse melanocortin receptor agonists derived from a novel thioether cyclized peptidomimetic scaffold
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The solid-phase synthesis of a novel thioether cyclized peptidomimetic scaffold, displaying functionality at the i to i + 3 positions, is reported. The thioether bridge is formed on-bead by an intramolecular reaction between a chloroacetylated reduced pep
- Bondebjerg, Jon,Xiang, Zhimin,Bauzo, Rayna M.,Haskell-Luevano, Carrie,Meldal, Morten
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Read Online
- Synthesis Using a Fmoc-Based Strategy and Biological Activities of Some Reduced Peptide Bond Pseudopeptide Analogues of Dynorphin A
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Eight analogues of Dyn A(1-11)-NH2 incorporating the enzymatically stable Ψ(CH2-NH) isosteric peptide bond replacement were synthesized and tested for binding affinity at the central opioid μ, δ, and κ receptors in guinea pig brain (GPB) homogenates and f
- Meyer, Jean-Philippe,Davis, Peg,Lee, Katharine B.,Porreca, Frank,Yamamura, Henry I.,Hruby, Victor J.
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Read Online
- Modulating Angiogenesis by Proteomimetics of Vascular Endothelial Growth Factor
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Angiogenesis, formation of new blood vessels from the existing vascular network, is a hallmark of cancer cells that leads to tumor vascular proliferation and metastasis. This process is mediated through the binding interaction of VEGF-A with VEGF receptor
- Abdulkadir, Sami,Cai, Jianfeng,Hu, Yong,Jiang, Wei,Li, Chunpu,Li, Qi,Sang, Peng,Wei, Lulu,Zhao, Xue
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supporting information
p. 270 - 281
(2022/01/19)
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- α/Sulfono-γ-AApeptide Hybrid Analogues of Glucagon with Enhanced Stability and Prolonged in Vivo Activity
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Peptide drugs have the advantages of target specificity and good drugability and have become one of the most increasingly important hotspots in new drug research in biomedical sciences. However, peptide drugs generally have low bioavailability and metabol
- Sang, Peng,Zeng, Hongxiang,Lee, Candy,Shi, Yan,Wang, Minghui,Pan, Cong,Wei, Lulu,Huang, Chenglong,Wu, Mingjun,Shen, Weijun,Li, Xi,Cai, Jianfeng
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p. 13893 - 13901
(2021/09/28)
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- α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions
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The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53-MDM2 PPIs. The best
- Sang, Peng,Shi, Yan,Lu, Junhao,Chen, Lihong,Yang, Leixiang,Borcherds, Wade,Abdulkadir, Sami,Li, Qi,Daughdrill, Gary,Chen, Jiandong,Cai, Jianfeng
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p. 975 - 986
(2020/03/10)
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- Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions
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Peptidomimetics have gained great attention for their function as protein-protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 α/Sulfono-I-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 α/Sulfono-I-AA peptides were shown to bind tightly to MDM2 and MDMX, with Kd of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-I-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 α/Sulfono-I-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 α/Sulfono-I-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 α/Sulfono-I-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.
- Shi, Yan,Sang, Peng,Lu, Junhao,Higbee, Pirada,Chen, Lihong,Yang, Leixiang,Odom, Timothy,Daughdrill, Gary,Chen, Jiandong,Cai, Jianfeng
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p. 13187 - 13196
(2020/12/02)
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- Synthesis and biological activity of peptide α-ketoamide derivatives as proteasome inhibitors
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Proteasome activity affects cell cycle progression as well as the immune response, and it is largely recognized as an attractive pharmacological target for potential therapies against several diseases. Herein we present the synthesis of a series of pseudo
- Pacifico, Salvatore,Ferretti, Valeria,Albanese, Valentina,Fantinati, Anna,Gallerani, Eleonora,Nicoli, Francesco,Gavioli, Riccardo,Zamberlan, Francesco,Preti, Delia,Marastoni, Mauro
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p. 1086 - 1092
(2019/08/01)
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- Selective Substrates and Activity-Based Probes for Imaging of the Human Constitutive 20S Proteasome in Cells and Blood Samples
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The proteasome is an enzyme complex critical for maintaining protein homeostasis. Perturbed proteasome function leads to pathologies including cancer and autoimmune and neurodegenerative disease. Therefore, the proteasome constitutes an excellent molecular target for pharmaceutical development. Here, using the HyCoSuL approach, we designed and synthesized novel and selective fluorogenic substrates for each of these three constitutive 20S proteasome activities and applied them to assess inhibition of proteasome subunits by MG-132 and a clinically used inhibitor bortezomib. Our results confirm the utility of designed substrates in biochemical assays. Furthermore, selective peptide sequences obtained in this manner were used to construct fluorophore-labeled activity-based probes and then utilized to detect each constitutive 20S proteasome subunit simultaneously in lysates of HEK-293F cells and red blood cells. Overall, we describe a simple and rapid method useful to measure constitutive 20S proteasome activity in whole human blood samples that could enable early diagnosis of pathological states associated with aberrantly upregulated proteasome activity.
- Rut, Wioletta,Poreba, Marcin,Kasperkiewicz, Paulina,Snipas, Scott J.,Drag, Marcin
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p. 5222 - 5234
(2018/06/04)
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- Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products
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Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synt
- Bockus, Andrew T.,Lexa, Katrina W.,Pye, Cameron R.,Kalgutkar, Amit S.,Gardner, Jarret W.,Hund, Kathryn C.R.,Hewitt, William M.,Schwochert, Joshua A.,Glassey, Emerson,Price, David A.,Mathiowetz, Alan M.,Liras, Spiros,Jacobson, Matthew P.,Lokey, R. Scott
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supporting information
p. 4581 - 4589
(2015/06/25)
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- Discovery of a novel class of potent HCV NS4B inhibitors: SAR studies on piperazinone derivatives
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HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p- fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.
- Kakarla, Ramesh,Liu, Jian,Naduthambi, Devan,Chang, Wonsuk,Mosley, Ralph T.,Bao, Donghui,Steuer, Holly M. Micolochick,Keilman, Meg,Bansal, Shalini,Lam, Angela M.,Seibel, William,Neilson, Sandra,Furman, Phillip A.,Sofia, Michael J.
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p. 2136 - 2160
(2014/04/03)
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- Alzheimer's disease: Identification and development of β-secretase (BACE-1) binding fragments and inhibitors by dynamic ligation screening (DLS)
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The application of dynamic ligation screening (DLS), a methodology for fragment-based drug discovery (FBDD), to the aspartic protease β-secretase (BACE-1) is reported. For this purpose, three new fluorescence resonance energy transfer (FRET) substrates we
- Fernandez-Bachiller, Maria Isabel,Horatscheck, Andre,Lisurek, Michael,Rademann, Joerg
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p. 1041 - 1056
(2013/07/26)
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- Helical oligomers of thiazole-based γ-amino acids: Synthesis and structural studies
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9-Helix: 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) were synthesized as new γ-amino acid building blocks. The structures of various ATC oligomers were analyzed in solution by CD and NMR spectroscopy and in the solid state by X-ray crystallography. The ATC sequences adopted a well-defined 9-helix structure in the solid state and in aprotic and protic organic solvents as well as in aqueous solution. Copyright
- Mathieu, Loic,Legrand, Baptiste,Deng, Cheng,Vezenkov, Lubomir,Wenger, Emmanuel,Didierjean, Claude,Amblard, Muriel,Averlant-Petit, Marie-Christine,Masurier, Nicolas,Lisowski, Vincent,Martinez, Jean,Maillard, Ludovic T.
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p. 6006 - 6010
(2013/07/19)
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- A peptide aldehyde microarray for high-throughput profiling of cellular events
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Microarrays provide exciting opportunities in the field of large-scale proteomics. With the aim to elucidate enzymatic activity and profiles within native biological samples, we developed a microarray comprising a focused positional-scanning library of enzyme inhibitors. The library was diversified across P1-P4 positions, creating 270 different inhibitor sublibraries which were immobilized onto avidin slides. The peptide aldehyde-based small-molecule microarray (SMM) specifically targeted cysteine proteases, thereby enabling large-scale functional assessment of this subgroup of proteases, within fluorescently labeled samples, including pure proteins, cellular lysates, and infected samples. The arrays were shown to elicit binding fingerprints consistent with those of model proteins, specifically caspases and purified cysteine proteases from parasites (rhodesein and cruzain). When tested against lysates from apoptotic Hela and red blood cells infected with Plasmodium falciparum, clear signatures were obtained that were readily attributable to the activity of constituent proteases within these samples. Characteristic binding profiles were further able to distinguish various stages of the parasite infection in erythrocyte lysates. By converting one of our brightest microarray hits into a probe, putative protein markers were identified and pulled down from within apoptotic Hela lysates, demonstrating the potential of target validation and discovery. Taken together, these results demonstrate the utility of targeted SMMs in dissecting cellular biology in complex proteomic samples.
- Wu, Hao,Ge, Jingyan,Yang, Peng-Yu,Wang, Jigang,Uttamchandani, Mahesh,Yao, Shao Q.
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p. 1946 - 1954
(2011/04/16)
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- Tin(ii) chloride assisted synthesis of N-protected γ-amino β-keto esters through semipinacol rearrangement
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A facile synthetic route for the preparation of N-protected γ-amino β-keto esters from amino aldehydes and ethyl diazoacetate is described. The two component coupling is facilitated by tin(ii) chloride followed by semipinacol rearrangement leading to the product in quantitative yield. The reaction is mild, instantaneous and compatible with Boc-, Fmoc- and Cbz-amino protecting groups.
- Bandyopadhyay, Anupam,Agrawal, Neha,Mali, Sachitanand M.,Jadhav, Sandip V.,Gopi, Hosahudya N.
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supporting information; experimental part
p. 4855 - 4860
(2010/12/24)
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- Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases
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Seven PNA-encoded combinatorial libraries targeting proteases and phosphatases with covalent reversible and irreversible mechanism-based inhibitors were prepared. The libraries were synthesized using modified PNA monomers, which dramatically increase the water solubility of the libraries in biologically relevant buffers. The libraries were shown to selectively inhibit targeted enzymes.
- Debaene, Fran?ois,Da Silva, Julien A.,Pianowski, Zbigniew,Duran, Fernando J.,Winssinger, Nicolas
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p. 6577 - 6586
(2008/02/05)
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- Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: Potential scaffolds for peptide mimetics
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The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to α- or β-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.
- Reggelin, Michael,Junker, Bernd,Heinrich, Timo,Slavik, Stefan,Buehle, Philipp
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p. 4023 - 4034
(2007/10/03)
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- METHOD FOR STEREOCHEMICALLY CONTROLLED PRODUCTION OF ISOMERICALLY PURE HIGHLY SUBSTITUTED AZACYCLIC COMPOUNDS
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A method for stereochemically controlled production of azacyclic compounds of general formula (I) in which the substituents have the meanings given in the specification. The invention also relates to intermediate products of this method and to novel azacy
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- Solid-phase synthesis of peptide vinyl sulfones as potential inhibitors and activity-based probes of cysteine proteases
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(Matrix presented) Peptide vinyl sulfones were prepared from 2-chlorotrityl resin-bound phenolic amino vinyl sulfones in high yield and purity. This method enables the convenient synthesis of peptide vinyl sulfones having different amino acids at the Psu
- Wang, Gang,Mahesh, Uttamchandani,Chen, Grace Y. J.,Yao, Shao Q.
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p. 737 - 740
(2007/10/03)
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- A versatile synthesis of 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones
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A mild and general strategy for the synthesis of 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones is described. The seven-membered lactam is prepared by intramolecular amide bond formation from the intermediate amino acid, which is obtained e
- Van Rompaey, Karolien,Van Den Eynde, Isabelle,De Kimpe, Norbert,Tourwé, Dirk
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p. 4421 - 4432
(2007/10/03)
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- Combinatorial Synthesis of a Small-Molecule Library Based on the Vinyl Sulfone Scaffold
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(Equation presented) A 30-member library of small molecules based on the vinyl sulfone scaffold was prepared on rink amide resin, using solid phase-based reactions such as oxidation and Horner-Wadsworth-Emmons reaction. The library was designed such that
- Wang, Gang,Yao, Shao Q.
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p. 4437 - 4440
(2007/10/03)
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- Synthesis of N-protected α-amino aldehydes from their morpholine amide derivatives
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A new method for the synthesis of N-protected α-amino aldehydes was developed. N-Protected α-amino amides of morpholine were easily prepared and then reduced with LiAlH4 to produce clean N-protected α-amino aldehydes. This new scheme of synthesis can be used with Boc, Z and Fmoc amino-protecting groups.
- Douat, Céline,Heitz, Annie,Martinez, Jean,Fehrentz, Jean-Alain
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- Synthesis of 9-fluorenylmethoxycarbonyl-protected amino aldehydes
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9-Fluorenylmethoxycarbonyl-protected amino aldehydes could be efficiently prepared in good yields by using two methods: (i) NaBH4 reduction of Fmoc-protected mixed anhydrides, followed by the Swern oxidation of the alcohols; and (ii) LiAlH
- Wen, James J.,Crews, Craig M.
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p. 1855 - 1858
(2007/10/03)
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- AN EFFICIENT METHOD FOR PREPARATION OF OPTICALLY ACTIVE N-PROTECTED α-AMINO ALDEHYDES FROM N-PROTECTED α-AMINO ALCOHOLS
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N-Protected α-amino aldehydes of high optical purity were prepared in excellent yields from corresponding α-amino alcohols by 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzodioxol-3(H)-one (periodinane) oxidation.
- Soucek, Milan,Urban, Jan
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p. 693 - 696
(2007/10/02)
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- Preparation of N2-protected amino acid aldehydes via reduction of corresponding acid halides with lithium tris-(tert.butoxy)-aluminium hydride
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N2-FMOC amino aldehydes, N2-BOC amino aldehydes and N2-Z amino aldehydes are readily preparable from N2-FMOC amino acid chlorides and N2-BOC and N2-Z amino acid fluorides respectively, by r
- Zlatoidsky, Pavol
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p. 7281 - 7284
(2007/10/02)
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- Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists
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A series of cyclic pseudopeptides of the formula cyclo(LeuΨ[CH2NH]Xaa- Gln-Trp-Phe-βAla), where Xaa represents the residue of an α-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 recepto
- Quartara,Fabbri,Ricci,Patacchini,Pestellini,Maggi,Pavone,Giachetti,Arcamone
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p. 3630 - 3638
(2007/10/02)
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- Synthesis of Chiral N-Protected α-Amino Aldehydes by Reduction of N-Protected N-Carboxyanhydrides (UNCAs)
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A facile one step synthesis of a wide variety of N-protected (Boc, Z, Fmoc) α-amino aldehydes under mild conditions is described.Pure N-protected (Boc, Z, Fmoc) α-amino aldehydes were obtained in high yields by reduction of N-protected (Z, Boc, Fmoc)-N-ca
- Fehrentz, Jean-Alain,Pothion, Catherine,Califano, Jean-Christophe,Loffet, Albert,Martinez, Jean
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p. 9031 - 9034
(2007/10/02)
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