- Addressing protein-protein interactions with small molecules: A pro-pro dipeptide mimic with a PPII helix conformation as a module for the synthesis of PRD-binding ligands
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X marks the spot: The synthetic tricyclic amino acid X (see structure; C gray, H cyan, N blue, O red, double bond yellow) can be incorporated, without loss of binding ability, as a Pro-Pro substitute into two peptides that bind to the proline-rich motif-recognizing domains Fyn-SH3. The dipeptide analogue X, which is locked in a polyproline type II helix conformation, is created by stereoselective introduction of a vinylidene bridge into a diproline unit.
- Zaminer, Jan,Brockmann, Christoph,Huy, Peter,Opitz, Robert,Reuter, Cedric,Beyermann, Michael,Freund, Christian,Mueller, Matthias,Oschkinat, Hartmut,Schmalz, Hans-Guenther,Kuehne, Ronald
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- MASP INHIBITORY COMPOUNDS AND USES THEREOF
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The present invention relates to novel Mannose-binding lectin (MBL)-associated serine protease (MASP) inhibitory compounds, as well as analogues and derivatives thereof, to processes for the preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of renal and cardiovascular disorders and of ischemia reperfusion injuries.
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Page/Page column 180
(2020/11/23)
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- INDUCTION OF ALPHA HELIX CONFORMATIONS IN PROTEINS AND PEPTIDES
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Substituted tricyclic diproline analogues of the formula (I): wherein the variables are as defined herein. Also disclosed are methods for the production thereof, the use thereof for the induction of an alpha-helix conformation in peptides and/or proteins, pharmaceuticals containing said compounds, methods for the production of a peptide library containing said compounds, and peptide libraries containing said compounds.
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Page/Page column 13-14
(2012/07/14)
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- Insights into the reaction mechanism of the prolyl - Acyl carrier protein oxidase involved in anatoxin-a and homoanatoxin-a biosynthesis
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Anatoxin-a and homoanatoxin-a are two potent cyanobacterial neurotoxins. We recently reported the identification of the gene cluster responsible for the biosynthesis of these toxins as well as the in-vitro reconstitution of the first steps of this biosynthesis. We now report experimental evidence supporting the proposed reaction mechanism of AnaB, a flavoprotein homologous to acyl-CoA dehydrogenase. AnaB catalyzes the two-electron oxidation of prolyl-AnaD, which is proline linked to the acyl carrier protein holo-AnaD, to dehydroprolyl-AnaD using oxygen as the second substrate. AnaB is thus an oxidase. By using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we have identified and characterized dehydroprolyl-AnaD, the AnaB product. We estimated an apparent catalytic constant of 1 min- 1 for AnaB catalysis. We synthesized several deuterium-labeled prolines and enzymatically transformed them into their corresponding prolyl-AnaD. These deuterium-labeled prolyl-AnaDs were oxidized in the presence of AnaB, and the deuterium labeling in the remaining substrate and in the product was determined by LC-MS/MS. The data supported a reaction mechanism starting with a rapid enolization followed by a slow oxidation to give the conjugated imine, which in turn was isomerized to pyrroline-5-carboxyl-AnaD. We also showed that cis- and trans-4-fluoro-l-prolyl- AnaD and 3,4-dehydro-l-prolyl-AnaD were transformed into pyrrole-2-carboxyl-AnaD by AnaB. Thus, the 4-fluoro-analogues experienced a β-elimination supporting the AnaB-catalyzed aza - allylic isomerization. We identified by sequence alignment the AnaB active site base, Glu244. We produced, purified, and characterized the E244A AnaB mutant, which is inactive, supporting the catalytic role of E244 as a base.
- Mann, Stephane,Lombard, Berangere,Loew, Damarys,Mejean, Annick,Ploux, Olivier
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experimental part
p. 7184 - 7197
(2012/07/02)
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- STRUCTURAL MIMETICS OF PROLINE-RICH PEPTIDES AND THE PHARMACEUTICAL USE THEREOF
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The invention relates to compounds of general formula (I), which can be used particularly as structural mimetics of proline-rich peptides and are therefore capable of binding PRM binding domains (proline-rich motif binding domains) of proteins. The invention also relates to the use of said compounds as pharmaceutical active agents and the use of these pharmaceutical active agents for treating bacterial diseases, neurodegenerative diseases and tumours.
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Page/Page column 30-31
(2011/02/26)
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- Synthesis of macrocyclic analogues of the neuroprotective agent glycyl-l-prolyl-l-glutamic acid (GPE)
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The syntheses of seven macrocyclic analogues of the neuroprotective tripeptide glycyl-l-prolyl-l-glutamic acid (GPE) 1 are described. Macrocycles 6 and 7 mimic the cis conformer of GPE whereas macrocycles 2-5, 8, and 9 mimic the trans conformer of GPE. The macrocyclic peptides of well-defined geometry were prepared via Grubbs ring closing metathesis of an appropriate diene precursor. In turn each of the diene precursors were prepared from the readily available allyl-substituted amino acid building blocks 12, 13, 14, 27, 36 and 51. The Royal Society of Chemistry 2006.
- Harris, Paul W. R.,Brimble, Margaret A.
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p. 2696 - 2709
(2008/02/08)
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- NOVEL CYANOPYRROLIDIDES, METHODS FOR THE PRODUCTION THEREOF, AND USE OF THE SAME AS MEDICAMENTS
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The invention relates to compounds of formula (I) wherein the radicals have the designations cited in the text. The invention also relates to the stereoisomer forms and the physiologically compatible salts thereof, the physiologically functional derivatives thereof, and methods for producing the same. The inventive compounds are suitable for treating illnesses of the metabolism such as type 2 diabetes.
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Page/Page column 16; 33-34
(2010/02/10)
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- Rigid dipeptide mimetics. Stereocontrolled synthesis of all eight stereoisomers of 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic Acid ester
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Stereopure 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid (AZABIC) methyl and ethyl esters (14a/b and 23a/b, respectively) have been synthesized from readily available (R)- and (S)-pyroglutamic esters 1 and 15. Altogether all eight possible stereoisomers of this type of compound have been prepared in gram quantities. (C) 2000 Elsevier Science Ltd.
- Mulzer, Johann,Schülzchen, Frank,Bats, Jan-W.
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p. 4289 - 4298
(2007/10/03)
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- Asymmetric synthesis of L-proline regio- and stereoselectively labelled with deuterium
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A synthesis of L-proline where all of the ring methylenes are stereoselectively labelled with deuterium is described. A catalytic deuteration of protected 3,4-dehydro-L-proline using transition metal catalyst followed by RuO4-oxidation gave a [3,4-D2]pyroglutamic acid derivative. A syn-selective deuteration of the aminal derived from the pyroglutamate with Et3SiD-BF3 · OEt2 furnished (2S,3S,4R,5S)-[3,4,5- D3]proline. The present procedure is also applied to the synthesis of the corresponding (2S,3S,4R,5R)-isomer.
- Oba, Makoto,Terauchi, Tsutomu,Miyakawa, Akiko,Nishiyama, Kozaburo
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p. 937 - 945
(2007/10/03)
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- C-glycosylation of cyclic N-acyliminium ions with trimethylsilyloxyfuran
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C-glycosylation of 2-methoxy-5-alkoxycarbonyl pyrrolidines with trimethylsilyloxyfuran allows us to obtain the corresponding pyrrolidines contigus to a α,β-unsaturated butyrolactone.
- Pichon, Marianne,Figadere, Bruno,Cave, Andre
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p. 7963 - 7966
(2007/10/03)
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- Diastereoselective functionalization of 5-hydroxy prolinates by tandem Horner-Emmons-Michael reaction
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The tandem Horner-Emmons-Michael reaction of the hemiaminal derived from N-BOC protected pyroglutamic esters with stabilised phosphonates gives 5-substituted prolinates in high diastereomeric and enantiomeric excess through 1,4-asymmetric induction process.
- Collado, Ivan,Ezquerra, Jesus,Vaquero, Juan Jose,Pedregal, Concepcion
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p. 8037 - 8040
(2007/10/02)
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