- Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile
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Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.
- Tran, Kien,Van Den Hauwe, Robin,Sainsily, Xavier,Couvineau, Pierre,C?té, Jér?me,Simard, Louise,Echevarria, Marco,Murza, Alexandre,Serre, Alexandra,Théroux, Léa,Saibi, Sabrina,Haroune, Lounès,Longpré, Jean-Michel,Lesur, Olivier,Auger-Messier, Mannix,Spino, Claude,Bouvier, Michel,Sarret, Philippe,Ballet, Steven,Marsault, éric
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supporting information
p. 5345 - 5364
(2021/02/16)
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- Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template
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De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50: 170 nm) and MMP-9 (IC50: 140 nm).
- Gall, Flavio M.,Hohl, Deborah,Frasson, David,Wermelinger, Tobias,Mittl, Peer R. E.,Sievers, Martin,Riedl, Rainer
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p. 4051 - 4055
(2019/02/16)
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- Preparation method for 2-amino-3-biphenylpropionic acid
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The invention discloses a preparation method for 2-amino-3-biphenylpropionic acid. The preparation method comprises the following steps: step 1, with p-bromobenzaldehyde and phenylboronic acid as rawmaterials and an organic solvent as a reaction solvent, subjecting the p-bromobenzaldehyde and the phenylboronic acid to a reaction under the actions of alkali and a catalyst so as to obtain biphenylcarbaldehyde (II); step 2, allowing the biphenylcarbaldehyde (II) to react with ethyl cyanoacetate under the action of the alkali so as to obtain an intermediate (III); step 3, allowing the intermediate (III) to generate a reduction reaction with hydrogen under the catalytic action of Pd/C in a hydrogen atmosphere so as to obtain an intermediate (IV); step 4, allowing the intermediate (IV) to be hydrolyzed into an amide compound (V) in absolute ethyl alcohol under the action of the alkali; and step 5, subjecting the amide compound (V) to a reaction under the actions of bromine and sodium hydroxide so as to obtain the 2-amino-3-biphenylpropionic acid. The preparation method provided by the invention has the advantages of cheap and easily-available raw materials, low production cost, short reaction steps, mild reaction conditions, convenient post-treatment, high yield and applicability to industrial production.
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Paragraph 0026; 0032; 0033; 0039; 0040; 0046
(2019/10/01)
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- Tailored Mutants of Phenylalanine Ammonia-Lyase from Petroselinum crispum for the Synthesis of Bulky l- and d-Arylalanines
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Tailored mutants of phenylalanine ammonia-lyase from Petroselinum crispum (PcPAL) were created and tested in ammonia elimination from various sterically demanding, non-natural analogues of phenylalanine and in ammonia addition reactions into the corresponding (E)-arylacrylates. The wild-type PcPAL was inert or exhibited quite poor conversions in both reactions with all members of the substrate panel. Appropriate single mutations of residue F137 and the highly conserved residue I460 resulted in PcPAL variants that were active in ammonia elimination but still had a poor activity in ammonia addition onto bulky substrates. However, combined mutations that involve I460 besides the well-studied F137 led to mutants that exhibited activity in ammonia addition as well. The synergistic multiple mutations resulted in substantial substrate scope extension of PcPAL and opened up new biocatalytic routes for the synthesis of both enantiomers of valuable phenylalanine analogues, such as (4-methoxyphenyl)-, (napthalen-2-yl)-, ([1,1′-biphenyl]-4-yl)-, (4′-fluoro-[1,1′-biphenyl]-4-yl)-, and (5-phenylthiophene-2-yl)alanines.
- Filip, Alina,Nagy, Emma Z. A.,Tork, Souad D.,Bánóczi, Gergely,To?a, Monica I.,Irimie, Florin D.,Poppe, László,Paizs, Csaba,Bencze, László C.
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p. 2627 - 2633
(2018/05/03)
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- Single-Biocatalyst Synthesis of Enantiopure d-Arylalanines Exploiting an Engineered d-Amino Acid Dehydrogenase
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A practical and efficient biocatalytic synthesis of aromatic d-amino acids has been developed, based on the reductive amination of the corresponding α-keto acids via a recombinant whole cell system composed of an engineered dehydrogenase and cofactor recycling apparatus. The reaction was shown to give excellent enantioselectivity (≥98%) and good yields at the preparative scale across a broad range of substrates. Additionally, the structure of the variant enzyme was solved to allow rationalisation of the observed reaction rates. The engineered whole cell catalyst was also used to mediate the production of d-phenylalanine derivatives from racemic mixtures and cheaper l-amino acids by combining it with an enantiocomplementary deaminase. (Figure presented.).
- Parmeggiani, Fabio,Ahmed, Syed T.,Thompson, Matthew P.,Weise, Nicholas J.,Galman, James L.,Gahloth, Deepankar,Dunstan, Mark S.,Leys, David,Turner, Nicholas J.
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p. 3298 - 3306
(2016/10/20)
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- Preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol
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The invention discloses a preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol represented by formula (I). The method comprises the following steps: carrying out an Erlenmeyer-Plochl cyclization reaction on biphenylcarboxaldehyde and N-acylglycine, hydrolyzing or alcoholyzing, and carrying out asymmetric hydrogenation to obtain (R)-N-acylbiphenylalanine or an ester thereof; and carrying out acid hydrolysis, reduction and amino protection on the (R)-N-acylbiphenylalanine or the ester thereof, or carrying out reduction, acid hydrolysis and amino protection on the (R)-N-acylbiphenylalanine or the ester thereof, or directly reducing the (R)-N-acylbiphenylalanine or the ester thereof in order to obtain the product (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol. The product is a key intermediate of Sacubitril (AHU-377) which is one of a novel blood pressure reducing medicine LCZ696. The method has the advantages of easily available raw materials, and suitableness for industrial production.
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Paragraph 0111; 0113; 0114; 0115
(2016/10/08)
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- Chemoenzymatic Synthesis of Optically Pure l- and d-Biarylalanines through Biocatalytic Asymmetric Amination and Palladium-Catalyzed Arylation
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A chemoenzymatic approach was developed and optimized for the synthesis of a range of N-protected nonnatural l- and d-biarylalanine derivatives. Starting from 4-bromocinnamic acid and 4-bromophenylpyruvic acid using a phenylalanine ammonia lyase (PAL) and an evolved d-amino acid dehydrogenase (DAADH), respectively, both enantiomers of 4-bromophenylalanine were obtained and subsequently coupled with a panel of arylboronic acids to give the target compounds in high yield and optical purity under mild aqueous conditions.
- Ahmed, Syed T.,Parmeggiani, Fabio,Weise, Nicholas J.,Flitsch, Sabine L.,Turner, Nicholas J.
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p. 5410 - 5413
(2015/09/15)
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- Suzuki-Miyaura Diversification of Amino Acids and Dipeptides in Aqueous Media
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The Suzuki-Miyaura derivatisation of free amino acids, peptides and proteins is an attractive area with considerable potential utility for medicinal chemistry and chemical biology. Here we report the modification of unprotected and Boc-protected aromatic amino acids and dipeptides in aqueous media, enabling heteroarylation and vinylation. We systematically investigate the impact of the peptide backbone and adjacent amino acid residues upon the reaction. Our studies reveal that although asparagine and histidine hinder the reaction, by utilising dppf, a ferrocene-based bidentate phosphine ligand, cross coupling of halophenylalanine or halotryptophan adjacent to such a residue could be enabled. Our studies reveal dppf to have good compatibility with all unprotected, proteinogenic amino acid side chains.
- Willemse, Tom,Van Imp, Karolien,Goss, Rebecca J. M.,Van Vlijmen, Herman W. T.,Schepens, Wim,Maes, Bert U. W.,Ballet, Steven
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p. 2055 - 2070
(2015/11/24)
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- Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors
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A class of tripeptidyl transition state inhibitors containing a P1 glutamine surrogate, a P2 leucine, and a P3 arylalanines, was found to potently inhibit Norwalk virus replication in enzyme and cell based assays. An array of warheads, including aldehyde, α-ketoamide, bisulfite adduct, and α-hydroxyphosphonate transition state mimic, was also investigated. Tripeptidyls 2 and 6 possess antiviral activities against noroviruses, human rhinovirus, severe acute respiratory syndrome coronavirus, and coronavirus 229E, suggesting a broad range of antiviral activities.
- Prior, Allan M.,Kim, Yunjeong,Weerasekara, Sahani,Moroze, Meghan,Alliston, Kevin R.,Uy, Roxanne Adeline Z.,Groutas, William C.,Chang, Kyeong-Ok,Hua, Duy H.
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supporting information
p. 6317 - 6320
(2013/11/19)
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- Identification of new peptide amides as selective cathepsin L inhibitors: The first step towards selective irreversible inhibitors?
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A small library of peptide amides was designed to profile the cathepsin L active site. Within the cathepsin family of cysteine proteases, the first round of selection was on cathepsin L and cathepsin B, and then selected hits were further evaluated for binding to cathepsin K and cathepsin S. Five highly selective sequences with submicromolar affinities towards cathepsin L were identified. An acyloxymethyl ketone warhead was then attached to these sequences. Although these original irreversible inhibitors inactivate cathepsin L, it appears that the nature of the warhead drastically impact the selectivity profile of the resulting covalent inhibitors.
- Torkar, Ana,Lenar?i?, Brigita,Lah, Tamara,Dive, Vincent,Devel, Laurent
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supporting information
p. 2968 - 2973
(2013/06/27)
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- Nonapeptide and decapeptide analogs of LHRH, useful as LHRH antagonists
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Nonapeptide and decapeptide analogs of LHRH which have the formula: STR1 and the pharmaceutically acceptable salts thereof, wherein: X is a D-alanyl residue wherein one hydrogen on C-3 is replaced by:(a) a carbocyclic aryl-containing radical selected from the group consisting of phenyl substituted with three or more straight chain lower alkyl groups, naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl and benzhydryl; or(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl, and adamantyl; or(c) a heterocyclic aryl containing radical selected from the group consisting of radicals represented by the following structural formulas: STR2 wherein A"" and A'' are independently selected from the group consisting of hydrogen, lower alkyl, chlorine, and bromine, and G is selected from the group consisting of oxygen, nitrogen, and sulfur;A is an aminoacyl residue selected from the group consisting of L-pyroglutamyl, D-pyroglutamyl, N-acyl-L-prolyl, N-acyl-D-prolyl, N-acyl-D-tryptophanyl, N-acyl-D-phenylalanyl, N-acyl-D-p-halophenylalanyl, and N-acyl-X wherein X is as defined previously;B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-halophenylalanyl, 2,2-diphenylglycyl, and X wherein X is as defined previously;C is an amino acyl residue selected from the group consisting of L-tryptophanyl, D-tryptophanyl, D-phenylalanyl and X wherein X is as defined above;E is glycinamide or --NH--R 1, wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or STR3 wherein R 2 is hydrogen or lower alkyl; are disclosed. These compounds are LHRH antagonists.
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