- Performance improvement of araujiain, a cystein phytoprotease, by immobilization within calcium alginate beads
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The effect of immobilization within alginate beads on the performance of araujiain in aqueous and non-aqueous media was studied. Optimum pH and temperature, thermal and pH-stability, kinetic parameters and operational stability were determined. Entrapped
- Quiroga, Evelina,Illanes, Cristián Omar,Ochoa, Nelio Ariel,Barberis, Sonia
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- A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities
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Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.
- An, Jing,Chen, Yiling,Ciechanover, Aaron,Fuk-Woo Chan, Jasper,Huang, Lina S.,Huang, Ziwei,Liang, Boqiang,Nie, Linlin,Wang, Juan,Warshel, Arieh,Wu, Meixian,Wu, Yi,Xu, Yan,Ye, Hui,Yuan, Shuofeng,Yuen, Kwok-Yung,Zhou, Jiao
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- Engineered Substrate for Cyclooxygenase-2: A Pentapeptide Isoconformational to Arachidonic Acid for Managing Inflammation
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Beyond the conventional mode of working of anti-inflammatory agents through enzyme inhibition, herein, COX-2 was provided with an alternate substrate. A proline-centered pentapeptide isoconformational to arachidonic acid, which exhibited appreciable selectivity for COX-2, overcoming acetic acid- and formalin-induced pain in rats to almost 80%, was treated as a substrate by the enzyme. Remarkably, COX-2 metabolized the pentapeptide into small fragments consisting mainly of di- and tripeptides that ensured the safe breakdown of the peptide under in vivo conditions. The kinetic parameter Kcat/Km for COX-2-mediated metabolism of the peptide (6.3 × 105 M-1 s-1) was quite similar to 9.5 × 105 M-1 s-1 for arachidonic acid. Evidenced by the molecular dynamic studies and the use of Y385F COX-2, it was observed that the breakage of the pentapeptide has probably been taken place through H-bond activation of the peptide bond by the side chains of Y385 and S530.
- Kaur, Baljit,Kaur, Manpreet,Kaur, Navjot,Garg, Saweta,Bhatti, Rajbir,Singh, Palwinder
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p. 6363 - 6376
(2019/07/08)
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- Convenient green preparation of dipeptides using unprotected α-amino acids
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Dipeptides and amides were obtained in high yields from N-carbobenzyloxy α-amino acids and 3-phenylpropanoic acid with unprotected α-amino acids via the corresponding mixed carbonic carboxylic anhydrides using ethyl chloroformate and triethylamine by an ecological and convenient method in which the protection of C-terminals is not needed.
- Ezawa, Tetsuya,Jung, Seunghee,Kawashima, Yuya,Noguchi, Takuya,Imai, Nobuyuki
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- Peptiligase, an Enzyme for Efficient Chemoenzymatic Peptide Synthesis and Cyclization in Water
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We describe a novel, organic cosolvent-stable and cation-independent engineered enzyme for peptide coupling reactions. The enzyme is a variant of a stable calcium-independent mutant of subtilisin BPN′, with the catalytic Ser212 mutated to Cys and Pro216 converted to Ala. The enzyme, called peptiligase, catalyzes exceptionally efficient peptide coupling in water with a surprisingly high synthesis over hydrolysis (S/H) ratio. The S/H ratio of the peptide ligation reaction is correlated to the length of the peptide substrate and proved to be >100 for the synthesis of a 13-mer peptide, which corresponds to >99% conversion to the ligated peptide product and 1% hydrolytic side-reaction. Furthermore, peptiligase does not require a particular recognition motif resulting in a broadly applicable and traceless peptide ligation technology. Peptiligase is very robust, easy to produce in Bacillus subtilis, and its purification is straightforward. It shows good activity and stability in the presence of organic cosolvents and chelating or denaturing agents, enabling the ligation of poorly soluble (hydrophobic) or folded peptides. This enzyme could be useful for the (industrial) synthesis of diverse (pharmaceutical) peptides. In addition, peptiligase is able to efficiently catalyze head-to-tail peptide cyclization reactions. (Figure presented.) .
- Toplak, Ana,Nuijens, Timo,Quaedflieg, Peter J. L. M.,Wu, Bian,Janssen, Dick B.
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p. 2140 - 2147
(2016/07/16)
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- A green route for the synthesis of a bitter-taste dipeptide combining biocatalysis, heterogeneous metal catalysis and magnetic nanoparticles
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There is increasing demand for green technologies to produce high-solubility and low-toxicity compounds with potential application in the food industry. This study aimed to establish a clean, synthetic route for preparing the bitter-taste dipeptide Ala-Phe, a potential substitute for caffeine as a food additive. Synthesis of Z-Ala-Phe-OMe starting from Z-Ala-OH and HCl·Phe-OMe was catalysed by thermolysin at 50 °C in buffer (step 1). Z-Ala-Phe-OMe ester hydrolysis to give Z-Ala-Phe-OH at 37 °C in 30% acetonitrile/buffer was catalysed by α-bovine chymotrypsin (αCT), protease with esterase activity (step 2). Hydrogenation of Z-Ala-Phe to give the desired Ala-Phe was catalysed by C/Pd in methanol (step 3). Steps 2 and 3 were optimized by using the magnetically recoverable recycling enzyme Fe3O4@silica-αCT and the magnetically recoverable metal nanocatalyst Fe3O4@silica-Pd, respectively. This inspiring combination of technologies and the original results demonstrate the suitability of using enzymes, metal catalyst and magnetic nanoparticles for easy, economical, stereoselective, clean production of an important target compound. Besides, they add to the development of peptide chemistry and catalysis.
- Ungaro, Vitor A.,Liria, Cleber W.,Romagna, Carolina D.,Costa, Natália J. S.,Philippot, Karine,Rossi, Liane M.,Machini, M. Teresa
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p. 36449 - 36455
(2015/05/13)
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- Synthesis, molecular docking and anticancer studies of peptides and iso-peptides
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Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results.
- Jabeen, Farukh,Panda, Siva S.,Kondratyuk, Tamara P.,Park, Eun-Jung,Pezzuto, John M.,Ihsan-Ul-Haq,Hall, C. Dennis,Katritzky, Alan R.
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p. 2980 - 2984
(2015/06/22)
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- A one-pot saponification-coupling sequence suitable for C-terminus peptide elongation using lithium carboxylates
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An efficient procedure has been developed for the saponification of common peptide esters, followed by straightforward coupling of the lithium carboxylate. Adding some water to the reaction medium gave faster saponification and did not interfere with the coupling reagent. As peptide chemistry constitutes a major application of the amidation reaction, amino acid substrates were chosen for this study, monitoring both yields and epimerization of the peptides obtained. Georg Thieme Verlag Stuttgart New York.
- Azzouz, Rabah,Petit, Sylvain,Rouchet, Jean-Baptiste,Bischoff, Laurent
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supporting information
p. 1843 - 1846
(2014/08/18)
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- Synthesis and antimalarial bioassay of quinine - peptide conjugates
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Amino acid and peptide conjugates of quinine were synthesized using microwave irradiation in 52-95% yields using benzotriazole methodology. The majority of these conjugates retain in vitro antimalarial activity with IC50 values below 100 nm, similar to quinine.
- Panda, Siva S.,Ibrahim, Mohamed A.,Kuecuekbay, Hasan,Meyers, Marvin J.,Sverdrup, Francis M.,El-Feky, Said A.,Katritzky, Alan R.
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p. 361 - 366
(2013/10/08)
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- Enzymatic synthesis of activated esters and their subsequent use in enzyme-based peptide synthesis
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Chemoenzymatic peptide synthesis is potentially the most cost-efficient technology for the synthesis of short and medium-sized peptides. However, there are still some limitations when challenging peptides, e.g. containing sterically demanding acyl donors, non-proteinogenic amino acids or proline residues, are to be synthesized. To remedy these limitations, special ester moieties have been used that are specifically recognized by the enzyme, e.g. guanidinophenyl, carboxamidomethyl (Cam) or trifluoroethyl (Tfe) esters, which, unfortunately, are notoriously difficult to synthesize chemically. Herein, we demonstrate that Cam and Tfe esters are very useful for Alcalase-CLEA mediated peptide synthesis using sterically demanding and non-proteinogenic acyl donors as well as poor nucleophiles, and combinations thereof. Furthermore, these esters can be efficiently synthesized by using the lipase Cal-B or Alcalase-CLEA. Finally, it is shown that the ester synthesis by Cal-B and subsequent peptide synthesis by Alcalase-CLEA can be performed simultaneously using a two-enzyme-one-pot approach with glycolamide or 2,2,2-trifluoroethanol as additive.
- Nuijens, Timo,Cusan, Claudia,Schepers, Annette C.H.M.,Kruijtzer, John A.W.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,Quaedflieg, Peter J.L.M.
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- Highly diastereoselective peptide chain extensions of unprotected amino acids with N-(Z-α-aminoacyl)benzotriazoles
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Coupling an unprotected amino acid or dipeptide in partially aqueous solution with a readily available N-(Z-α-amino-acyl)benzotriazole or N-(Z-α-aminopetidoyl)benzotriazole affords N-terminal-protected di-, tri-, and tetrapeptides in yields of 85-98% (average 95% for 2a-i, 93% for 4a-f and 4a′, 86% for 5a-b) with minimal epimerization.
- Katritzky, Alan R.,Suzuki, Kazuyuki,Singh, Sandeep K.
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p. 2645 - 2652
(2007/10/03)
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- Soluble alpha-amino acid salts in acetonitrile: practical technology for the production of some dipeptides.
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Alpha-amino acids are soluble in acetonitrile when treated with phosphazene bases. As a result, the protection/deprotection events that are usually required for peptide coupling reactions can be minimized. This is illustrated in the synthesis of the important angiotensin-converting enzyme (ACE) inhibitor enalapril. [reaction: see text]
- Palomo, Claudio,Palomo, Antonio L,Palomo, Francisco,Mielgo, Antonia
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p. 4005 - 4008
(2007/10/03)
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- Resin-to-resin acyl- and aminoacyl-transfer reactions using oxime supports
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We describe a convergent approach to solid-phase synthesis in which two fragments of a molecule are synthesized on independent supports and then condensed in a key resin-to-resin transfer reaction. This approach has been utilized for the synthesis of amides and ureas by transferring acyl groups and aminoacyl groups from p-nitrophenyl(polystyrene)ketoxime resin to amino acid-functionalized Wang resins. Oxime resinderived esters of peptides undergo transacylation to a solution-phase nucleophilic activator which then transfers the peptide to another resin bearing a nucleophilic amine terminus, resulting in amide bond formation. Likewise, oxime resin-derived carbamates, prepared from phosgenated p-nitrophenyl(polystyrene)ketoxime resin, undergo thermolytic isocyanate liberation in solution, which reacts with a second resin bearing a nucleophilic amino terminus resulting in urea bond formation.
- Hamuro, Yoshitomo,Scialdone, Mark A.,DeGrado, William F.
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p. 1636 - 1644
(2007/10/03)
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- An Effective Water-Free Aprotic System for Dissolving Free Amino Acids
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An effective water-free system was proposed for dissolution and subsequent use in peptide synthesis of free amino acids and their derivatives. It consists of dimethylformamide, a tertiary base, and inorganic additives. Neutral salts (CF3COONa, Ba(ClO4)2, Ca(ClO4)2, NaClO4, BaI2, or Ca(NO3)2) serve as the inorganic additives that increase the solubility of free amino acids in dimethylformamide and provide true 0.2-3 M amino acid solutions. Triethylamine and N-methylmorpholine are most suitable as the tertiary bases. This system was used in reactions with acylating agents: Boc2O, ZOSu, FmocOSu, and activated derivatives of Nα-protected amino acids or peptides. The corresponding amino acid derivatives or Nα-protected di-, tri-, and tetrapeptides were obtained in yields of 80-99 percent at the reaction times of 30-240 min.
- Raydnov, M. G.,Klimenko, L. V.,Mitin, Yu. V.
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p. 283 - 287
(2007/10/03)
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- Urethane-protected amino acid-N-carboxyanhydrides
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Urethane-protected NCAs and MTAs are prepared by reacting an NCA or NTA with a haloformate in an inert diluent, under anhydrous conditions and in the presence of a tertiary nitrogen-containing base having an atom or functional group sufficiently electron rich and positioned relative to the nitrogen of said base so as to render said atom or group capable of complexing with the H--N group of said N-carboxyanhydride or N-thiocarboxyanhydride but able to generate N-carboxyanhydride or N-thiocarboxyanhydride anionic complexes capable of reacting with the haloformate.
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- Urethane-protected amino acid-N-carboxyanhydrides
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The invention relates to urethane-protected amino acid-N-carboxyanhydride and N-thiocarboxyanhydride compounds which are useful in peptide, polypeptide and protein synthesis. Disclosed herein is the preparation and use of these novel compounds.
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- 3,5-substituted 4,5-dihydroisoxazoles as transglutaminase inhibitors
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The present invention is directed to certain 3,5 substituted, 4,5-dihydroisoxazoles, and methods for their use. These compounds are transgulatminase inhibitors, and are particularly effective in the inhibition of epidermal transglutaminase and the treatment of acne.
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- Peptide-bond Formation, Chemoselective Acylation of Amino Acids, and Crosslinking Reaction between Amino Acids Utilizing a Functional Five-membered Heterocycle, 1,3-Thiazolidine-2-thione
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The monitored aminolysis of 3-acyl-1,3-thiazolidine-2-thiones has been extended to the peptide-bond formation, the chemoselective acylation of amino acids having multifunctional groups, and the crosslinking reaction between amino acids.
- Nagao, Yoshimitsu,Miyasaka, Tadayo,Seno, Kaoru,Fujita, Eiichi,Shibata, Daisuke,Doi, Etsushiro
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p. 2439 - 2446
(2007/10/02)
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- Synthesis of Amides of Dipeptides and Kinetics of Papain-catalysed Hydrolysis of These Amides
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The N-benzyloxycarbonylated amides of the dipeptides L-alanyl-L-phenylalanine, L-leucylleucine, L-leucyl-L-phenylalanine, L-phenylalanyl-L-alanine and L-phenylalanyl-L-leucine have been synthesised and the kinetic parameters for the papain-catalysed hydrolysis of these substrates and their ester analogs have been determined at pH 8 and 9.All the amide substrates are hydrolysed at the amide linkage except N-benzyloxycarbonyl-L-alanyl-L-phenylalanine amide which hydrolyses to the extent of 45percent at the amide linkage and 55percent at the peptide linkage.For amide hydrolysis acetylation and deacetylation rate constants are approximately equal.
- Zaher, M. R.,El-Sharief, A. M. Sh.
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p. 740 - 743
(2007/10/02)
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- Imido carbonate compound, production thereof and uses thereof as reagent for forming active ester of amino acids
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A new carbonate compound which is N,N'-di-succinimidyl carbonate, N,N'-diphthalimidyl carbonate or N,N'-bis(5-norbornene-2,3-dicarboxyimidyl) carbonate is produced by reacting an N-hydroxy compound of the formula wherein R is succinimido, phthalimido or 5-norbornene-2,3-dicarboximido group, with a silylating agent, followed by reacting the resultant silylated product with phosgene, or alternatively by reacting said N-hydroxy compound with trichloromethyl chloroformate either in the molten state or in the presence of a non-polar organic solvent such as xylene. This new carbonate compound is useful not only as a reagent for forming active esters from amino acid but also as a reagent for introducing a carbonyl group between a pair of amino groups, a pair of amino and hydroxyl groups or a pair of amino and mercapto groups, for producing an isothiocyanate from a dithicarbamic acid by removal of hydrogen sulfide from the latter, and for producing acrylic acid derivatives from N-protected serine by dehydration of the latter.
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- MONITORED AMINOLYSIS OF 3-ACYL-1,3-THIAZOLIDINE-2-THIONE WITH AMINO ACID AND ITS DERIVATIVE: PEPTIDE BOND FORMATION, CHEMOSELECTIVE ACYLATION, AND BRIDGING REACTION
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As a new extention of the monitored aminolysis of 3-acyl-1,3-thiazolidine-2-thione, its applications to peptide bond formation, chemoselective acylation of amino acid, and bridging reaction on the enzyme model are reported.
- Nagao, Yoshimitsu,Miyasaka, Tadayo,Seno, Kaoru,Yagi, Masahiro,Fujita, Eiichi
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p. 463 - 466
(2007/10/02)
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