- Optimization and Structure-Activity Relationships of Phosphinic Pseudotripeptide Inhibitors of Aminopeptidases That Generate Antigenic Peptides
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The oxytocinase subfamily of M1 aminopeptidases, consisting of ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2), and insulin-regulated aminopeptidase (IRAP), plays critical roles in the generation of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously demonstrated that phosphinic pseudotripeptides can constitute potent inhibitors of this group of enzymes. In this study, we used synthetic methodologies able to furnish a series of stereochemically defined phosphinic pseudotripeptides and demonstrate that side chains at P1′ and P2′ positions are critical determinants in driving potency and selectivity. We identified low nanomolar inhibitors of ERAP2 and IRAP that display selectivity of more than 2 and 3 orders of magnitude, respectively. Cellular analysis demonstrated that one of the compounds that is a selective IRAP inhibitor can reduce IRAP-dependent but not ERAP1-dependent cross-presentation by dendritic cells with nanomolar efficacy. Our results encourage further preclinical development of phosphinic pseudotripeptides as regulators of adaptive immune responses.
- Kokkala, Paraskevi,Mpakali, Anastasia,Mauvais, Francois-Xavier,Papakyriakou, Athanasios,Daskalaki, Ira,Petropoulou, Ioanna,Kavvalou, Sofia,Papathanasopoulou, Mirto,Agrotis, Stefanos,Fonsou, Theodora-Markisia,Van Endert, Peter,Stratikos, Efstratios,Georgiadis, Dimitris
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supporting information
p. 9107 - 9123
(2016/10/22)
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- Synthesis and evaluation of peptidic irreversible inhibitors of tissue transglutaminase
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Herein we report the synthesis and the evaluation of eight novel compounds as irreversible inhibitors of transglutaminase (TGase). These compounds are based on a minimal peptidic scaffold shown previously [Chem. Biol. 2005, 12, 469-475] to confer affinity for the TGase active site and bear electrophilic groups such as α,β-unsaturated amide, chloroacetamide or maleimide; their general structure being Cbz-Phe-spacer-electrophile. The affinity conferred by the Cbz-Phe scaffold was determined by comparison to N-propylacrylamide and the length of the spacer was also varied to evaluate its importance. The inhibitory efficiencies (kinact/KI) of these compounds vary up to 105 M-1 min-1, among the highest reported for derivatives based on this simple Cbz-Phe peptidic scaffold.
- Pardin, Christophe,Gillet, Steve M.F.G.,Keillor, Jeffrey W.
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p. 8379 - 8385
(2008/02/05)
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- NOVEL ARYLAMIDINE DERIVATIVE OR SALT THEREOF
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An arylamidine derivative represented by a general formula described below or a salt thereof has an excellent antifungal action and high safety, and it is useful as an antifungal agent with good pharmacokinetics and pharmacodynamic properties: wherein X represents an unsubstituted or substituted lower alkylene or alkenylene group; G1 represents an oxygen atom, a sulfur atom, or an imino group; G2 represents a carbon atom or a nitrogen atom; Ra represents at least one group selected from the group consisting of a hydrogen atom, a halogen atom, and unsubstituted or substituted alkyl, cycloalkyl and alkoxy groups; R1 represents an unprotected or protected or unsubstituted or substituted amidino group; and R2 represents a substituted amino or substituted cyclic amino group, or the like.
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Page 116-117
(2010/02/09)
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- Fairly marked enantioselectivity for the hydrolysis of amino acid esters by chemically modified enzymes
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The hydrolysis (deacylation) of enantiomeric substrates by the chemically modified enzymes decanoyl-α-chymotrypsin and decanoyl-trypsin was studied. Reaction activity for decanoyl-α-chymotrypsin was lower than that for the native enzyme, although intriguingly the enantioselectivity was markedly enhanced as compared with the native enzyme. In particular, the apparently complete enantioselective catalysis was attained for the hydrolytic cleavage of p-nitrophenyl N-dodecanoyl- D(L)-phenylalaninates. The enhancement of enantioselectivity, however, was not observed for decanoyl-trypsin. These results suggest that the chemically modified α-chymotrypsin by addition of hydrophobic groups has promoted enantioselectivity for the hydrolysis of hydrophobic esters.
- Yano, Yoshihiro,Shimada, Kenji,Okai, Jiro,Goto, Koichi,Matsumoto, Yoko,Ueoka, Ryuichi
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p. 1314 - 1318
(2007/10/03)
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- Peptide coupling of unprotected amino acids through in situ p-nitrophenyl ester formation
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Several series of dipeptides and tripeptides were prepared via an activation-coupling method involving the in situ formation of a p-nitrophenyl ester of an (N-protected) amino acid, followed by coupling with an unprotected amino acid in partially aqueous solutions. The resulting peptide is easily isolated by precipitation. In general, the yields obtained are good to excellent and racemization is minimal. This method is particularly advantageous with respect to its simplicity and lack of obligatory side chain protection/deprotection steps.
- Gagnon, Paul,Huang, Xicai,Therrien, Eric,Keillor, Jeffrey W.
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p. 7717 - 7719
(2007/10/03)
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- Hybrid Liposomes Coupled to Steric Control with High Enantioselectivity
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With respect to the hydrolysis of enantiomeric substrates (p-nitrophenyl N-dodecanoyl-D(L)-phenylalaninate; C12-D(L)-Phe-PNP) by the tripeptide catalyst (N-(benzyloxycarbonyl)-L-phenylalanyl-L-histidyl-L-leucine; Z-PheHisLeu), a remarkably high enantioselectivity (kLa/obsd/kDa/obsd = 28) along with marked rate-enhancement of the hydrolytic cleavage of C12-D(L)-Phe-PNP was obtained with specific coaggregates of 32 mol percent L-α-dipalmitoylphosphatidylcholine (DPPC) and 68 mol percent α--ω-hydroxypoly(oxy-1,2-ethanediyl) (TritonX-100).The enantioselectivity was maximized at the phase transition temperature (Tc) in the 65 mol percent DPPC/35 mol percent TritonX-100 and 32 mol percent DPPC/68 mol percent TritonX-100 coaggregate systems.The hydrophobicity and fluidity of the coaggregates can apparently be changed around Tc on the basis of isokinetic temperature and fluorescence parameter studies.
- Goto, Koichi,Matsumoto, Yoko,Ueoka, Ryuichi
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p. 3342 - 3346
(2007/10/02)
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- Thermodynamic and (1)H NMR Study of Proton Complex Formation of Histidine-containing Cyclodipeptides in Aqueous Solution
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A thermodynamic and (1)H NMR study of proton complex formation in aqueous solution of some L-histidine-containing cyclic L-dipeptides has been carried out.The enthalpic and entropic changes associated with protonation of the cyclodipeptides, obtained by potentiometric and calorimetric measurements, together with the (1)H NMR data and NOESY experiments, enable the role played by non-covalent interactions in proton complex formation to be assessed.In addition, a comparison with c(Gly-His) permits the influence of side-chain residues on the conformation of protonated species to be observed.
- Arena, Giuseppe,Impellizzeri, Giuseppe,Maccarrone, Giuseppe,Pappalardo, Giuseppe,Sciotto, Domenico,Rizzarelli, Enrico
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p. 371 - 376
(2007/10/02)
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- Synthesis and Conformational Analysis of Epindolidione-Derived Peptide Models for β-Sheet Formation
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Synthesis of 2,8-diaminoepindolidione (2,8-diaminodibenzonaphthyridine-6,12(5,11H)-dione) in 19percent yield from p-nitroaniline is reported, as well as further conversion to 2,8-bis(Boc-L-Pro-Xxx)epindolidione (Xxx=Gly, D-Ala) and then to 2,8-bis(OC(Yyy-Zzz-NMe2)-L-Pro-Xxx)epindolidione (Yyy=Gly, L-Ala, D-Ala; Zzz=Gly, L-Phe, D-Phe).The β-turn-forming tendencies of the series 2,8-bis(X-L-Pro-D-Ala)epindolidione, where X=Ac, Boc, and COGlyOEt, are assigned from 1H NMR evidence.
- Kemp, D. S.,Bowen, Benjamin R.,Muendel, Christopher C.
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p. 4650 - 4657
(2007/10/02)
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- N,N'-Bis(2-oxo-3-oxazolidinyl)phosphorodiamidic Azide: A Useful Coupling Agent in Peptide Synthesis
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N,N'-Bis(2-oxo-3-oxazolidinyl)phosphorodiamidic azide (BOPA), has been developed as an efficient coupling reagent in peptide synthesis.Coupling reaction proceeds smoothly with no detectable racemization.
- Katti, S. B.,Misra, P. K.,Haq, W.,Mathur, K. B.
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- ACTIVATION OF A CARBOXY GROUP BY DIALKYL PYROCARBONATES. SYNTHESIS OF SYMMETRICAL ANHYDRIDES AND ARYL ESTERS OF N-PROTECTED AMINO ACIDS USING DI-tert-BUTYL PYROCARBONATE AS CONDENSING REAGENT
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It has been shown that di-tert-butyl pyrocarbonate can be used as a condensing reagent in the production of anhydrides and some aryl esters of carboxylic acids.The synthesis of anhydrides and of phenyl, p-nitrophenyl, β-naphtyl, and quinolin-8-yl esters of N-protected amino acids is described.
- Pozdnev, V. F.,Chernaya, M. Yu.
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p. 333 - 337
(2007/10/02)
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- Formation of peptide bonds in the presence of isonitriles
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Amino acids having masked amino groups react with amino acids having masked carboxyl groups to form peptide derivatives in good yields if the reaction medium contains an isonitrile. Isonitriles also are effective in causing condensation of amino acids having masked amino groups with compounds having active hydroxyl groups to the corresponding amino acid esters. The yields of the first-mentioned reaction are enhanced if the reaction mixture additionally contains one of the compounds having active hydroxyl groups. Both the peptide derivatives and the amino acid esters of the compounds having active hydroxyl groups are useful for peptide synthesis.
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- Novel esterifying agents, and their production and use
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A process for esterifying organic carboxylic acids which comprises reacting an organic carboxylic acid with a carbonic acid ester of the formula: EQU1 wherein R is an organic group and X and Y are each a negative group in the presence of a basic substance to make esterified the carboxyl group in the organic carboxylic acid. The process is advantageous in affording the objective carboxylic ester in a good yield within a short time by a simple operation under a mild reaction condition.
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