- Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6
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Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.
- Osko, Jeremy D.,Porter, Nicholas J.,Narayana Reddy, Poli Adi,Xiao, You-Cai,Rokka, Johanna,Jung, Manfred,Hooker, Jacob M.,Salvino, Joseph M.,Christianson, David W.
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p. 295 - 308
(2020/02/20)
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- Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent
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Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg-1 dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 104 M-1 and ΔG of -100.3 kJ mol-1 in comparison to a Ka 0.41 × 103 ± 0.09 M-1 and ΔG of -19.2 ± 0.06 kJ mol-1 for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg-1 dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.
- Singh, Palwinder,Kaur, Sukhmeet,Kaur, Jagroop,Singh, Gurjit,Bhatti, Rajbir
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p. 3920 - 3934
(2016/05/24)
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- Metalloporphyrin receptors for histidine-containing peptides
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Two new ditopic metalloporphyrin receptors constructed by combining metalloporphyrin with crown ethers have been prepared and characterized. 1H NMR and MS spectra confirmed the complexation of receptor with peptide driven by coordination interaction and hydrogen bonding. UV/vis experiments revealed that the receptors exhibited high binding affinity to histidine-containing peptides. These receptors could differentiate short peptides of C-terminal histidine and N-terminal histidine and formed the most stable complexes with tripeptide.
- Liu, Hui,Li, Zhan-Ting
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supporting information
p. 659 - 662
(2014/06/09)
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- Amide-based cationic lipids
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The present invention provides novel amide-based cationic lipids of the general structure: or a salt, or solvate, or enantiomers thereof wherein; (a) Y is a direct link or an alkylene of 1 to about 20 carbon atoms; (b) R1 is H or a lipophilic moiety; (c) R2, R3, and R4 are positively charged moieties, or at least one but not all of R2, R3, or R4 is a positive moiety and the remaining are independently selected from H, an alkyl moiety of 1 to about 6 carbon atoms, or a heterocyclic moiety of about 5 to about 10 carbon atoms; (d) n and p are independently selected integers from 0 to 8, such that the sum of n and p is from 1 to 16; (e) X? is an anion or polyanion and (f) m is an integer from 0 to a number equivalent to the positive charge(s) present on the lipid; provided that if Y is a direct link and the sum of n and p is 1 then one of either R3 or R4 must have an alkyl moiety of at least 10 carbon atoms.The present invention further provides compositions of these lipids with polyanionic macromolecules, methods for interfering with protein expression in a cell utilizing these compositions and a kit for preparing the same.
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- Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: A strategy for the design of peptidase inhibitors
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The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe-amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K(i) = 1 μM) and Ala-Pro-Ala-OH (K(i) = 3 μM) and dipeptide amide Val-Nvl-NHBu (K(i) = 3 μM) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K(i) = 0.57 μM) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8-inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design.
- Ganellin, C. Robin,Bishop, Paul B.,Bambal, Ramesh B.,Chan, Suzanne M. T.,Law, James K.,Marabout, Benoit,Luthra, Pratibha Mehta,Moore, Andrew N. J.,Peschard, Olivier,Bourgeat, Pierre,Rose, Christiane,Vargas, Froylan,Schwartz, Jean-Charles
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p. 664 - 674
(2007/10/03)
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- Amide-based cationic lipids
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The present invention provides novel amide-based cationic lipids of the general structure: STR1 or a salt, or solvate, or enantiomers thereof wherein; (a) Y is a direct link or an alkylene of 1 to about 20 carbon atoms; (b) R1 is H or a lipophilic moiety; (c) R2, R3, and R4 are positively charged moieties, or at least one but not all of R2, R3, or R4 is a positive moiety and the remaining are independently selected from H, an alkyl moiety of 1 to about 6 carbon atoms, or a heterocyclic moiety of about 5 to about 10 carbon atoms; (d) n and p are independently selected integers from 0 to 8, such that the sum of n and o is from 1 to 16; (e) X- is an anion or polyanion and (f) m is an integer from 0 to a number equivalent to the positive charge(s) present on the lipid; provided that if Y is a direct link and the sum of n and p is 1 then one of either R3 or R4 must have an alkyl moiety of at least 10 carbon atoms. The present invention further provides compositions of these lipids with polyanionic macromolecules, methods for interfering with protein expression in a cell utilizing these compositions and a kit for preparing the same.
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- α-Chymotrypsin-catalysed peptide synthesis using activated esters as acyl donors
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The coupling efficiency in α-chymotrypsin-catalysed peptide synthesis is greatly improved by the use of activated esters such as the 2,2,2-trifluoroethyl ester as acyl donor instead of the conventional methyl ester; this approach is useful for the incorporation of non-protein amino acids into peptides.
- Miyazawa, Toshifumi,Nakajo, Shin'ichi,Nishikawa, Miyako,Imagawa, Kiwamu,Yanagihara, Ryoji,Yamada, Takashi
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p. 2867 - 2868
(2007/10/03)
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- Iodide Dealkylation of Benzyl, PMB, PNB, and t-Butyl N-Acyl Amino Acid Esters via lithium Ion Coordination
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Lithium iodide promotes ester dealkylation in compounds containing an amide carbonyl in the γ-position to the ester carbonyl, as is found in N-acyl amino acid esters.Activation of the ester carbonyl via lithium ion coordination is facilatated by aprotic non-polar solvents such as THF and EtOAc.This process is not limited to methyl esters but readily dealkylates benzyl, PMB, PNB, and t-butyl esters and is espesially suitable for use with β-lactam esters because of the mild conditions. - Key Words: ester dealkylation; deesterification; lithium iodide; N-acyl amino acid esters; beta-lactams.
- Fisher, Jack W.,Trinkle, Kristina L.
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p. 2505 - 2508
(2007/10/02)
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- USE OF 4-CHLOROBUTYL ESTERS IN PEPTIDE SYNTHESIS
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Ho and Wong synthesised 4-chlorobutyl esters of simple carboxylic acids and removed the ester group by the action of sodium sulfide under reflux conditions.We describe here the synthesis of the 4-chlorobutyl esters of glycine and L-phenylalanine and its use in the synthesis of six new N-protected dipeptides 4-chlorobutyl esters (XHNCH2CO-HNCHRCO2(CH2)4Cl; R = H, CH2Ph; X = Z, Boc, Trt).The selective removal of the 4-chlorobutyl group can be achieved by the action of the sulfide anion in aqueous acetonitrile (room temperature, 1.5 to 5 h).The conditions are milder than those described, but similar to the conditions used with the dipeptides 2-bromoethyl esters.The N-protected dipeptides were isolated in 50 to 80percent yield.
- Trigo, M. Joaquina S. A. Amaral,Santos, M. Isabel A. Oliveira
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p. 2357 - 2359
(2007/10/02)
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- PEPTIDE SYNTHESIS CATALYZED BY NATIVE PROTEINASE K IN WATER-MISCIBLE ORGANIC SOLVENTS WITH LOW WATER CONTENT
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Rection of Ac-Tyr-OEt with HBr.Gly-NH2, catalysed by free proteinase K in various water-miscible organic solvents in the presence of triethylamine and 5 mol percent of water, was studied.Some aliphatic alcohols and acetonitrile proved to be suitable solvents.The effect of water content (2 percent - 20 percent) on the synthesis of Ac-Tyr-Gly-NH2 was studied using acetonitrile as solvent.Lowering of the water content to 5 percent or 2 percent led to almost 100 percent yield of the desired dipeptide; higher water content accelerated the reaction reducing at the same time the yield of Ac-Tyr-Gly-NH2 due to the concurrent hydrolysis of the ester Ac-Tyr-OEt.No reaction was observed in the absence of base (triethylamine), wereas an excess of base only retarded the reaction.The enzyme is capable of catalyzing the peptide bond synthesis with N-acylamino acids or N-acyl peptides as acylating components, which may contain all types of L-amino acid residues (except Pro) in the P1 position.However, the peptide bond synthesis depends strongly on the amino component composition, particularly on the amino acid residue in the P'1 position.Only amides of glycine and of hydrophillic amino acids were acylated with Ac-Tyr-OEt; amides of hydrophobic amino acids enter the reaction only reluctantly or not at al.The presence of Leu or Phe in position P'2 and Leu in position P'3 has not so negative effect on acylation of the amino component as has in presence in the P'1 position.The choice of protecting groups for the α-carboxyl of the amino component is restricted only to amide and in some cases its undesired enzymatic removal was observed.Unprotected peptides seem to be suitable amino components.
- Cerovsky, Vaclav,Martinek, Karel
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p. 2027 - 2041
(2007/10/02)
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- NEW APPROACH TO THE USE OF 2-BROMOETHYL ESTERS IN PEPTIDE SYNTHESIS
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The synthesis of six fully protected dipeptides 2-bromoethyl esters and a new method for the removal of the C-protection by the action of the sulphide anion, at room temperature, are described.
- Amaral Trigo, M. Joaquina S. A.,Oliveira Santos, M. Isabel A.
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p. 2787 - 2790
(2007/10/02)
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- PEPTIDE BOND FORMATION UNDER PHASE-TRANSFER CONDITIONS. REACTION KINETICS IN THE TWO-PHASE SYSTEM AND IN THE AQUEOUS AND ORGANIC PHASES
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In the two-phase system consisting of an organic solvent and a glycine buffer solution (pH 9) in the presence of cetyltrimethylammonium bromide glycine is capable of being extracted from the aqueous into the organic phase.Chloroform, 1-butanol, and nitrom
- Kosmynin, V. V.,Kaida, L. N.,Savelova, V. A.,Danilov, V. A.,Kononenko, E. I.,Litvinenko, L. M.
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p. 1583 - 1588
(2007/10/02)
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- PEPTIDE BOND FORMATION UNDER PHASE-TRANSFER CONDITIONS. EFFECT OF AMINO ACID STRUCTURE
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The extraction of amino acids NH2CH(R)COOH in the two-phase system consisting of 1-butanol and an amino acid buffer solution in the presence of cetyltrimethylammonium bromide and also the kinetics of the aminolysis of N-benzyloxycarbonylglycine p-nitrophe
- Kosmynin, V. V.,Kaida, L. N.,Savelova, V. A.,Taran, N. A.
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p. 2306 - 2311
(2007/10/02)
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- PEPTIDE BOND FORMATION UNDER PHASE-TRANSFER CONDITIONS. EFFECT OF CATALYST STRUCTURE
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The extraction of glycine into two-phase system consisting of 1-butanol and a glycine buffer solution in the presence of quarternary ammonium salts R3R'N+*X- was studied.The kinetics of the aminolysis of N-benzyloxycarbonylglycine an
- Kosmynin, V. V.,Kaida, L. N.,Savelova, V. A.,Miroshnichenko, M. A.
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p. 2311 - 2316
(2007/10/02)
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- SYNTHESIS AND USE OF DIBENZYLPYROCARBONATE: PREPARATION OF DIPEPTIDE FREE N-BENZYLOXYCARBONYL GLYCINE
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Dibenzylpyrocarbonate was prepared and reacted with amino acids.The quantity of dipeptides formed was evaluated.
- Sennyey, Gerard,Barcelo, Gerard,Senet, Jean-Pierre
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p. 5375 - 5376
(2007/10/02)
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- Polypeptide and its production and use
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Novel polypeptide of the formula: H-Tyr-Gly-Gly-Phe-Met-Lys-Pro-Tyr-Thr-Lys-Gln-Ser-His-Lys-Pro-Leu-Ile-Thr-Leu-Leu-Lys-His-Ile-Thr-Leu-Lys-Asn-Glu-Gln-OH is useful as an analgesic agent. Methods of its preparation are also disclosed.
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- THE OXAZOLE-TRIAMIDE REARRANGEMENT. APPLICATION TO PEPTIDE SYNTHESIS
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The carboxyl group of a N-acylated amino acid may be protected by conversion to an oxazole derivative which, on photooxygenation, regenerates the carboxyl group in activated (triamide) form for peptide synthesis.
- Wasserman, H. H.,Lu, T.-J.
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p. 3831 - 3834
(2007/10/02)
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- INVESTIGATION ON COUPLING PEPTIDES TO AMINOMETHYL POLYMERS
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Different peptide bond forming methods for attachment of model peptides to aminomethyl polymers have been compared.It has been observed that the yield of reaction depends on such features of polymer as quantity of functional groups and degree of its cross-linking.The sequential Edman degradation of a model peptide corresponding to 5 to 9 fragment of substance P was performed by the solid-phase technique.
- Orlowska, Alicja,Drabarek, Stefania
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p. 2329 - 2336
(2007/10/02)
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