- Direct observation of intramolecular hydrogen bonds in peptide 3 10 helices by 3hJN,C′ scalar couplings
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Differentiating helices: The direct observation of hydrogen bonds by 3hJN,C′ scalar couplings (see picture) is not only possible for α-helix and β-sheet peptides and proteins, but for 310-helical peptides as well. The meth
- Bellanda, Massimo,Rainaldi, Mario,Broxterman, Quirinus B.,Kaptein, Bernard,Formaggio, Fernando,Crisma, Marco,Mammi, Stefano,Toniolo, Claudio
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Read Online
- First interchain peptide interaction detected by ESR in fully synthetic, template-assisted, two-helix bundles
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We have designed and synthesized by solution methods two simple two-helix bundles based on a conformationally constrained cyclo-dipeptide template to the side chains of which two short, 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid spin-monolabeled, 310-helical peptides are covalently tethered. The preferred conformation of the appended chains has been assessed by FTIR absorption. The conclusions are corroborated by an X-ray diffraction analysis of one of the terminally blocked pentapeptide tails. For the first time, a solvent-dependent, inter-helix interaction has been monitored by conventional ESR spectroscopy on fully synthetic peptide systems. Half-field ESR measurements of these side-chain-substituted templates provided an experimental average distance between the two labels that is in good accord with that determined in a molecular modeling study.
- Polese, Alessandra,Anderson, D. Joe,Millhauser, Glenn,Formaggio, Fernando,Crisma, Marco,Marchiori, Fernando,Toniolo, Claudio
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Read Online
- NOVEL POLYMORPH FORM OF ( R)-2-[2-AMINO-3-(INDOL-3-YL)PROPIONYLAMINO]-2-METHYLPROPIONIC ACID AND USES THEREOF
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This invention relates to a novel polymorph form of compound (R)-2-[2-amino-3-(indol-3- yl)propionylamino]-2-methylpropionic acid, a process for making the novel polymorph form of the compound, and uses thereof for making other polymorph forms of the compound. The invention further relates to composition comprising novel polymorph form of the compound and a pharmaceutically acceptable carrier or excipient.
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Paragraph 00217; 00219; 00222
(2021/04/02)
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- Dipeptide analogs for treating conditions associated with amyloid fibril formation
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Dipeptide analogs comprising a tryptophan (Trp) moiety coupled to a beta-sheet breaker moiety derived from alpha-aminoisobutyric acid (Aib) are disclosed. The dipeptide analogs exhibit an improved performance in inhibiting amyloid fibril formation, as compared to previously described dipeptides. Compositions containing the dipeptide analogs and uses thereof in treating amyloid-associated diseases and disorders are also disclosed.
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Page/Page column 21-22
(2015/09/22)
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- Deracemization and the first CD spectrum of a 310-helical peptide made of achiral α-amino-isobutyric acid residues in a chiral membrane mimetic environment
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Interaction of the racemic helical homo-octapeptide made by the achiral Cα-methyl alanine (Aib) amino acid with a chiral enantiopure micellar aggregate made of N-dodecylproline led to the deracemization of the helical Aib sequence thus allowing
- Ceccacci, Francesca,Mancini, Giovanna,Rossi, Paola,Scrimin, Paolo,Sorrenti, Alessandro,Tecilla, Paolo
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supporting information
p. 10133 - 10135
(2013/10/22)
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- 5-(BIPHENYL-4-YL)-3-PHENYL-1,2,4-OXADIAZOLYL DERIVATIVES AS LIGANDS ON THE SPHINGOSINE 1-PHOSPHATE (S1P) RECEPTORS
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The present invention provides compounds of Formula (I), as selective S1 P1 inhibitors, as well as their use for treating multiple sclerosis and other diseases.
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Page/Page column 77
(2012/02/01)
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- Trichogin GA IV: A versatile template for the synthesis of novel peptaibiotics
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Trichogin GA IV, isolated from the fungus Trichoderma longibrachiatum, is the prototype of lipopeptaibols, the sub-class of short-length peptaibiotics exhibiting membrane-modifying properties. This peptaibol is predominantly folded in a mixed 310-/α-helical conformation with a clear, albeit modest, amphiphilic character, which is likely to be responsible for its capability to perturb bacterial membranes and to induce cell death. In previous papers, we reported on the interesting biological properties of trichogin GA IV, namely its good activity against Gram positive bacteria, in particular methicillin-resistant S. aureus strains, its stability towards proteolytic degradation, and its low hemolytic activity. Aiming at broadening the antimicrobial activity spectrum by increasing the peptide helical amphiphilicity, in this work we synthesized, by solution and solid-phase methodologies, purified and fully characterized a set of trichogin GA IV analogs in which the four Gly residues at positions 2, 5, 6, 9, lying in the poorly hydrophilic face of the helical structure, are substituted by one (position 2, 5, 6 or 9), two (positions 5 and 6), three (positions 2, 5, and 9), and four (positions 2, 5, 6, and 9) Lys residues. The conformational preferences of the Lys-containing analogs were assessed by FT-IR absorption, CD and 2D-NMR techniques in aqueous, organic, and membrane-mimetic environments. Interestingly, it turns out that the presence of charged residues induces a transition of the helical conformation adopted by the peptaibols (from 3 10-to α-helix) as a function of pH in a reversible process. The role played in the analogs by the markedly increased amphiphilicity was further tested by fluorescence leakage experiments in model membranes, protease resistance, antibacterial and antifungal activities, cytotoxicity, and hemolysis. Taken together, our biological results provide evidence that some of the least substituted among these analogs are good candidates for the development of new membrane-active antimicrobial agents. The Royal Society of Chemistry 2012.
- De Zotti, Marta,Biondi, Barbara,Peggion, Cristina,Formaggio, Fernando,Park, Yoonkyung,Hahm, Kyung-Soo,Toniolo, Claudio
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scheme or table
p. 1285 - 1299
(2012/03/07)
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- Toward the selective delivery of chemotherapeutics into tumor cells by targeting peptide transporters: Tailored gold-based anticancer peptidomimetics
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Complexes [AuIIIX2(dtc-Sar-AA-O(t-Bu))] (AA = Gly, X = Br (1)/Cl (2); AA = Aib, X = Br (3)/Cl (4); AA = l-Phe, X = Br (5)/Cl (6)) were designed on purpose in order to obtain gold(III)-based anticancer peptidomimetics that might specifically target two peptide transporters (namely, PEPT1 and PEPT2) upregulated in several tumor cells. All the compounds were characterized by means of FT-IR and mono- and multidimensional NMR spectroscopy, and the crystal structure of [AuIIIBr2(dtc-Sar-Aib-O(t- Bu))] (3) was solved and refined. According to in vitro cytotoxicity studies, the Aib-containing complexes 3 and 4 turned out to be the most effective toward all the human tumor cell lines evaluated (PC3, DU145, 2008, C13, and L540), reporting IC50 values much lower than that of cisplatin. Remarkably, they showed no cross-resistance with cisplatin itself and were proved to inhibit tumor cell proliferation by inducing either apoptosis or late apoptosis/necrosis depending on the cell lines. Biological results are here reported and discussed in terms of the structure-activity relationship.
- Negom Kouodom, Morelle,Ronconi, Luca,Celegato, Marta,Nardon, Chiara,Marchiò, Luciano,Dou, Q. Ping,Aldinucci, Donatella,Formaggio, Fernando,Fregona, Dolores
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scheme or table
p. 2212 - 2226
(2012/05/05)
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- Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy
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As a further extension of our research work focusing on the development of gold(III)-dithiocarbamato dtc derivatives of oligopeptides as potential anticancer agents, complexes [AuIIIX2(dtc-Sar-l-Ser(t-Bu)- O(t-Bu))] (X = Br (1a)/Cl (
- Kouodom, Morelle Negom,Boscutti, Giulia,Celegato, Marta,Crisma, Marco,Sitran, Sergio,Aldinucci, Donatella,Formaggio, Fernando,Ronconi, Luca,Fregona, Dolores
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p. 248 - 260
(2013/01/15)
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- ENZYME INHIBITORS
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Compounds of formula (I), inhibit HDAC activity: wherein A, B and D independently represent =CH- or =N-; W is-CH=CH- Or -CH2CH2-; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R2 and R3 are selected from the side chains of a natural or non-natural alpha amino acid, provided that neither R2 nor R3 is hydrogen, or R2 and R3, taken together with the carbon to which they are attached, form a 3-6 membered saturated cycloalkyl or heterocyclyl ring; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(=O)NR'-, -C(=S)-NR', -C(=NH)NR' or -S(=O)2NR - wherein R' is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein m, n, p, Q, AIk1 and AIk2 are as defined in the claims; X1 represents a bond; -C(=O); or -S(=O)2-; -NR4C(=O)-, -C(=O)NR4-,- NR4C(=O)NR5-, -NR4S(=O)2-, or -S(=O)2NR4- wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; and z is 0 or 1.
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Page/Page column 47
(2010/09/17)
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- ENZYME AND RECEPTOR MODULATION
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Covalent conjugates of an α,α-disubstituted glycine ester and a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid and the α,α-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme or receptor pass into cells and the active acid hydrolysis product accumulates within the cells.
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Page/Page column 14
(2010/12/29)
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- Replacement of Ala by Aib improves structuration and biological stability in thymine-based α-nucleopeptides
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Three thymine-based nucleo-heptapeptides, each containing two nucleo-amino acids and zero, one or four Aib residues, respectively, have been synthesized. A single Aib residue is enough to promote the adoption of a helical structure in our nucleopeptides a
- Geotti-Bianchini, Piero,Moretto, Alessandro,Peggion, Cristina,Beyrath, Julien,Bianco, Alberto,Formaggio, Fernando
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scheme or table
p. 1315 - 1321
(2010/06/17)
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- INHIBITORS OF P38 MAP KINASE
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Compounds of formula (I) are p38 MAP kinase inhibitors useful for the treatment of autoimmune and inflammatory diseases: wherein: G is -N= or -CH=; D is an optionally substituted divalent mono- or bi-cyclic aryl or heteroaryl radical having 5 - 13 ring members; R6 is hydrogen or optionally substituted CrC3 alkyl; P represents hydrogen and U represents a radical of formula (IA); or U represents hydrogen and P represents a radical of formula (IA); wherein A represents an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members; z is O or 1; -X1-L1-Y- is a linker radical or bond; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; and R2 and R3 are as defined in the claims.
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Page/Page column 37
(2009/10/21)
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- SUBSTITUTED THIOPHENECARBOXAMIDES AS IKK-BETA SERINE-, THREONINE-PROTEIN KINASE INHIBITORS
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Compounds of formula (IA) or (IB) are IKK inhibitors useful in the treatment of autoimmune and inflammatory diseases: wherein R7 is hydrogen or optionally substituted (C1-C6)alkyl; A is an optionally substituted aryl or heteroaryl of 5-13 ring atoms; Z is a radical of formula R1C( R2)(R3)NH-Y-L1-X1-(CH2)z- wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; and R2 and R3 independently represent the side chain of a natural or non-natural alpha amino acid but neither of R2 and R3 is hydrogen, or R2 and R3 taken together with the carbon atom to which they are attached form a C3-C7 cycloalkyl ring, and z, Y, L1 and X1 are as defined in the claims.
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Page/Page column 28
(2009/12/05)
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- Conformationally controlled, thymine-based α-nucleopeptides
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Rigid peptide backbones and backbone-to-side chain H-bonds permit the design of α-nucleopeptides with known 3D-structure; thymine-thymine base pairing is also observed.
- Geotti-Bianchini, Piero,Crisma, Marco,Peggion, Cristina,Bianco, Alberto,Formaggio, Fernando
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supporting information; experimental part
p. 3178 - 3180
(2009/12/01)
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- Preferred conformations of peptides containing tert-leucine, a sterically demanding, lipophilic α-amino acid with a quaternary side-chain C β atom
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Terminally protected homopeptides of tert-leucine, from the dimer to the bexamer, co-oligopeptides of tert-leucine in combination with α-aminoisobutyric acid or glycine residues up to the hexamer level, and simple dipeptides representing known scaffolds for catalysts in asymmetric organic reactions were prepared by solution methods and fully characterized. The results of conformation analysis, performed by use of FT-IR absorption, NMR, CD, and X-ray diffraction techniques, indicate that this Hydrophobic α-amino acid with tetrasubstitution at the Cβ atom is structurally versatile. We show that it prefers extended or semiextended conformations, but can also be accommodated in folded structures, pro vided that these are biased by the presence of helicogenic residues. The current large-scale production of Tle, combined with its conformational preferences unravelled in this work, should make this bulky, hydrophobic, C α-trisubstituted α-amino acid a regular building block of any strategy seeking to tailor peptides with improved catalytic and pharmacological properties.
- Formaggio, Fernando
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p. 2395 - 2404
(2007/10/03)
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- Serendipitous discovery of peptide dialkyl peroxides
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In an attempt to synthesize a homologous series of peptide peresters, we investigated the reaction of the oxazol-5(4H)-ones of Pht-(Aib)n-OH (n=2-8) and tert-butyl hydroperoxide in the presence of 4-(dimethylamino)pyridine. Unexpectedly, the ma
- Moretto, Alessandro,De Zotti, Marta,Scipionato, Laura,Formaggio, Fernando,Crisma, Marco,Toniolo, Claudio,Antonello, Sabrina,Maran, Flavio,Broxterman, Quirinus B.
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p. 3099 - 3112
(2007/10/03)
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- Folate-based inhibitors of thymidylate synthase: Synthesis and antitumor activity of γ-linked sterically hindered dipeptide analogues of 2-desamino- 2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)
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In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of γ-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) was pre
- Bavetsias, Vassilios,Jackman, Ann L.,Marriott, Jonathan H.,Kimbell, Rosemary,Gibson, William,Boyle, F. Thomas,Bisset, Graham M. F.
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p. 1495 - 1510
(2007/10/03)
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- Thymidylate synthase inhibiting quinazolinones
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Quinazolines of the formula STR1 wherein R1 is typically methyl, hydrogen or amino; R2 is typically methyl or propargyl; Ar is typically phenylene or 2'-fluorophenylene; R3 is the residue of a dipeptide substituted, typically by methyl, at position (a), (b) or (c), shown in the following partial formula: STR2 R4, R5, R6 and R8 are typically hydrogen, R7 is typically hydrogen or methyl; or a pharmaceutically acceptable salt, ester or amide thereof are of value in the treatment of cancer.
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- SYNTHESE VON 2-METHYLALANIN-PEPTIDEN, DIE pH-ABHAENGIGKEIT IHRER 13C-NMR-SPECTREN UND EINE NEUE METHODE ZUR AUSWERTUNG UEBER CS-DIAGRAMME
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The uncommon amino-acid 2-methylalanine (α-aminoisobutiryc acid, Aib) was investigated by 13C-NMR.The chemical shifts of amino- or carboxy-protected derivates of Aib and of protected oligopeptides are discussed with respect to neighbouring groups and amino acids.The pH-dependence of the 13C-NMR spectra of Aib, Aib-Ala, Ala-Aib, Aib-Ala-Aib and Aib-Ala-Aib-Ala-Aib was studied.Using these examples, a new and advantageous method is demonstrated for the first time for the evaluation of NMR titration curves, which uses so-called chemical shift diagrams (CS diagrams).
- Leibfritz, Dieter,Haupt, Erhard,Dubischar, Norbert,Lachmann, Heinrich,Oekonomopulos, Raymond,Jung, Guenther
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p. 2165 - 2182
(2007/10/02)
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