Inhibition of VAP1: quickly gaining ground as an anti-inflammatory therapy.
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Amine Oxidase (Copper-Containing)↗
Biomedical subjects
Miriam Royo
Publications and source records attributed to Miriam Royo.
New efficient substrates for semicarbazide-sensitive amine oxidase/VAP-1 enzyme: analysis by SARs and computational docking.
Structure activity relationships for semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) were studied using a library of arylalkylamine substrates, with the aim of contributing to the discovery of more efficient SSAO substrates. Experimental data were contrasted with computational docking studies, thereby allowing us to examine the mechanism and substrate-binding affinity of SSAO and thus contribute to the discovery of more efficient SSAO substrates and provide a structural basis for their interactions. We also built a model of the mouse SSAO structure, which provides several structural rationales for interspecies differences in SSAO substrate selectivity and reveals new trends in SSAO substrate recognition. In this context, we identified novel efficient substrates for human SSAO that can be used as a lead for the discovery of antidiabetic agents.
Adipocytes↗
Phosphorylation of either Ser16 or Thr30 does not disrupt the structure of the Itch E3 ubiquitin ligase third WW domain.
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Amino Acid Motifs↗
Preparation of de novo globular proteins based on proline dendrimers.
A synthetic method for the preparation of protein-like globular dendrimers derived from a combination of proline, glycine and imidazolidin ring as branching unit is described. The methodology allows the synthesis of novel peptide dendrimers up to fourth generation. Dendrimers were synthesized by a convergent solid-phase peptide synthesis approach. The conformational properties of branched polyproline peptides and proline dendrimers were studied by CD experiments. CD data suggest conformational plasticity of branched peptides for PPI and PPII, and a stable well-defined secondary structure of proline dendrimers for PPII.
Chromatography, High Pressure Liquid↗
Cell-penetrating cis-gamma-amino-l-proline-derived peptides.
The synthesis of cis-gamma-amino-l-proline oligomers functionalized at the proline alpha-amine with several groups that mimic the side chains of natural amino acids, including alanine, leucine, and phenylalanine, is herein described. These gamma-peptides enter into different cell lines (COS-1 and HeLa) via an endocytic mechanism. The ability of these compounds to be taken up into cells was studied at 37 degrees C and 4 degrees C by plate fluorimetry, flow cytometry, and confocal microscopy. In addition to their capacity for cellular uptake, these unnatural short length oligomers offer advantages over the well-known penetrating TAT peptide, such as being less toxic than TAT and protease resistance.
Alanine↗
Combinatorial approaches towards the discovery of new tryptase inhibitors.
The synthesis and evaluation as tryptase inhibitors of a library of 2,5-diketopiperazine derivatives containing guanidine or amidine functional groups is reported. Among the compounds evaluated, derivatives 6{CG4-CG8} and 6{CG4-CG9} are the most active compounds and have marked selectivity towards tryptase in front of trypsin.
Combinatorial Chemistry Techniques↗
Synthesis and screening of a small library of proline-based biodendrimers for use as delivery agents.
A small library of defined peptide dendrimers based on polyproline sequences was designed to demonstrate the feasibility of generating a new type of polymeric agent for therapeutic use. Structural modifications to dendrimer surfaces further enriched the diversity of the library. Data show that the prolinerich dendrimers can be internalized in human epithelial (HeLa) cells, demonstrating the importance of the dendrimeric motif. The promising results described herein suggest that controlled modification of the dendrimer surface should eventually yield proline dendrimers with therapeutic potential.
Animals↗
Peptide and amide bond-containing dendrimers.
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Amides↗
Solid-phase combinatorial synthesis of peptide-biphenyl hybrids as calpain inhibitors.
[structure: see text] The combinatorial parallel synthesis of peptide-biphenyl hybrids on solid support using state of the art of peptide synthesis is reported. Key steps were the N to C addition of an amino moiety, hydrolysis of the methyl ester, and the absence of cross-linked compounds when the 2,2'-diamino-1,1'-biphenyl was incorporated. When tested for activity as calpain inhibitors, some of the compounds exhibited IC(50) values in the nanomolar range.
Amino Acid Sequence↗
A new class of foldamers based on cis-gamma-amino-L-proline.
A synthetic method for the preparation of conformationally constrained gamma-peptides derived from gamma-amino-L-proline is described. The methodology allows the independent buildup of the peptide backbone and the introduction of sequential variations by reactions with the alpha-amino group of gamma-aminoproline. Both alkyl- and acyl-substituted gamma-peptides have been prepared and studied by CD and NMR. Conformational restrictions due to the cyclic structure of the monomer give rise to long-range interactions that are indicative of secondary structures even in aqueous solution. Interresidue NOEs suggest a concatenation of turns that, in a permissive solvent, could give rise to an isolated hydrogen bond ribbon, flanked and protected by proline rings.
Aminobutyrates↗
Solid-phase synthesis of second-generation polyproline dendrimers.
Second-generation dendrimers have been prepared on solid phase by successive additions of branched polyproline building blocks starting from two different branching units anchored to the solid support. The preparation of Pro-rich building blocks was carried out by stepwise solid-phase synthesis and their iterative addition was performed by a convergent approach, also using solid-phase synthesis. cis-4-Amino-L-proline and imidazolidine-2-carboxylic acid were used as branching units due to their structural resemblance to proline. The optimized strategy allowed the target compounds to be obtained with high purities without the need for purification steps.
Chromatography, High Pressure Liquid↗
Tentoxin as a scaffold for drug discovery. Total solid-phase synthesis of tentoxin and a library of analogues.
[reaction: see text] A solid-phase method for the synthesis of tentoxin has been developed. Two key steps-dehydration and N-alkylation-are carried out while the peptide is anchored to the resin. The method, which has been validated by the preparation of a library of tentoxin analogues, should be applicable to the generation of further libraries that have the tentoxin scaffold structure, as well as other structures containing N-alkylated didehydroamino acids.
Amino Acid Sequence↗
Exploring solid-phase approaches for the preparation of new beta-lactams from amino acids.
Two solid-phase approaches, involving the base-assisted intramolecular alkylation of N-chloroacetyl-Phe derivatives anchored to appropriate solid supports, were investigated for the preparation of novel beta-lactams. When a BAL-type strategy was used, the resin-bound azetidinones were easily formed, as established by MAS-NMR, but final compounds could not be removed from the resin, unless a suitable two linkers system was used. In the second approach, in which the Phe residue is anchored to a Wang-type resin through the carboxylate group, the corresponding 1,4,4-trisubstituted 2-azetidinone was obtained in moderate to good yield and high purity.
Amino Acids↗
Peptide dendrimers based on polyproline helices.
We present a new family of peptide dendrimers based on polyproline helices and cis-4-amino-L-proline as a branching unit. Dendrimers were synthesized by a convergent solid-phase peptide synthesis approach. The conformational transition between polyproline type I helix and polyproline type II helix was observed by circular dichroism in branched polyproline building blocks with more than 14 proline residues and in the resulting dendrimers. Both linear and dendritic polyprolines were found to be actively internalized by rat kidney cells. Preliminary results show that the antibiotic ciprofloxacin form complexes with branched polyproline chains in 99.5% propanol.
Animals↗
Multicomponent reactions with dihydroazines: efficient synthesis of a diverse set of pyrido-fused tetrahydroquinolines.
A multicomponent assembly of pyrido-fused tetrahydroquinolines is accomplished in a one-pot process from the interaction of dihydroazines, aldehydes, and anilines. A rational screening of the different components and parameters of this reaction, such as the range of reactive starting materials, catalysts and reaction conditions (solvent range; thermal, high pressure- and microwave-promoted processes) is carried out. Optimized conditions allow an efficient preparation of pyrido-fused tetrahydroquinolines with good yields, bypassing the biomimetic NADH-like reductive pathway which is typical in the interaction of dihydropyridines with carbonyl compounds and amines. Furthermore, solid-supported versions of the process have been developed, which should facilitate the preparation of libraries.
Aldehydes↗