Biomedical subjects

Y Hamuro

Publications and source records attributed to Y Hamuro.

15 recordsLinked to original sources

PubMed2001

High resolution, high-throughput amide deuterium exchange-mass spectrometry (DXMS) determination of protein binding site structure and dynamics: utility in pharmaceutical design.

Mass spectrometry-based peptide amide deuterium exchange techniques have proven to be increasingly powerful tools with which protein structure and function can be studied, and are unparalleled in their ability to probe sub-molecular protein dynamics. Despite this promise, the methodology has remained labor-intensive and time consuming, with substantial limitations in comprehensiveness (the extent to which target protein sequence is covered with measurable peptide fragments) and resolution (the degree to which exchange measurements can be ascribed to particular amides). I have developed and integrated a number of improvements to these methodologies into an automated high throughput, high resolution system termed Deuterium Exchange Mass Spectrometry (DXMS). With DXMS, complete sequence coverage and single-amide (amino acid) resolution are now rapidly accomplished. DXMS is designed to work well with large proteins and when only small amounts of material are available for study. Studies can be performed upon a receptor-ligand pair as they exist on or within a living cell (in vivo) without prior purification, allowing effective in situ study of integral membrane protein receptors. We have ambitious initiatives underway to make DXMS widely available both for basic academic research studies and commercial drug discovery efforts. In this paper I present an overview of DXMS technology and highlight some of the benefits it will provide in drug discovery and basic proteomics research.

Amides↗

PubMed2001

Functionalized oligoanthranilamides: modular and conformationally controlled scaffolds.

This paper describes the use of functionalized oligoanthranilamides as conformationally controlled scaffolds for molecular recognition. Oligomers of anthranilamides are stabilized by the formation of intramolecular six-membered hydrogen bonds in a linear strand conformation. Onto alternate anthranilic acid units, we have attached di- or tripeptide recognition units with the potential to form intramolecular hydrogen bonds to an intercalated peptide strand. Using 1H NMR dilution experiments in CDCl(3), we have observed chemical shift changes that are consistent with the formation of an extended hydrogen bonded sheet dimer. We also demonstrate that the bis-alanine functionalized strands are able to form discrete hydrogen bonded complexes with dipeptide substrates and to bind hexanoyl alanylalanine selectively over its benzyl ester. In the presence of excess hydrogen bond donors and acceptors, the oligoanthranilamide strand retained its linear conformation, pointing to the potential of this modular design as a useful and stable scaffold for molecular recognition studies.

Dimerization↗

PubMed1999

The twists and turns of beta-peptides.

Recently, it has been discovered that peptides composed of beta-amino acids are capable of adopting novel secondary structures demonstrating that peptides composed of alpha-amino acids are not unique in their ability to fold into well-defined structures. Cyclic as well as acyclic peptides composed of beta-amino acid residues adopt turn, helical, and sheet-like conformations. Here, we discuss the synthesis and conformational preferences of individual, substituted beta-amino acids as well as the structures that peptides composed of these residues, beta-peptides, may adopt.

Amino Acids↗

PubMed1998

Protein surface recognition by synthetic agents: design and structural requirements of a family of artificial receptors that bind to cytochrome c.

The design, synthesis, and evaluation of a novel series of receptors for protein surface recognition are described. The design of these agents is based around the attachment of four constrained peptide loops onto a central calix[4]arene scaffold. This arrangement mimics the role of the hypervariable loops in antibody combining regions and defines a large surface area for binding to a complementary region of the exterior of a target protein. Using affinity and gel filtration chromatographies we show that one particular receptor binds strongly to the surface of cytochrome c. The site of binding is presumably close to the heme edge region, which contains several charged lysine residues. This is supported by the observation that the receptor inhibits the reduction of Fe(III) cytochrome c to its Fe(II) form. We also show that binding is strongly dependent on the nature of the substituents on the lower rim of the calixarene. The nmr and computational studies suggest that this effect may be due to conformational differences among the differently substituted receptors.

Animals↗

PubMed1980

Studies on antihyperlipidemic agents. II. Synthesis and biological activities of 2-chloro-3-arylpropionic acids.

alpha-Substituted-beta-arylpropionic acid derivatives were prepared and examined for hypolipidemic activity. The structure-activity relationship study showed that a chloro substituent at the alpha-position and an aryloxy or aralkyloxy substituent on the beta-aryl moiety was necessary for possession of substantial activity. In addition, some of these compounds showed hypolipidemic and hypoglycemic effects on diabetic mice. Among the 71 compounds prepared, ethyl 2-chloro-3-[4-(4-chlorobenzyloxy)phenyl]propionate (12) and ethyl 2-chloro-3-[4-(1-phenylethyloxy)phenyl]propionate (24) were the best with respect to activity and toxicity.

Animals↗

PubMed1980

Studies on antihyperlipidemic agents. III. Synthesis and biological activities of 2-chloro-3-arylpropionic acids containing a quarternary carbon atom.

A series of 2-chloro-3-(4-alkoxyphenyl)propionic acids containing a quarternary carbon atom in the alkoxy moiety was prepared and the hypolipidemic and hypoglycemic activities were evaluated. Of the 18 compounds synthesized, ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate (1) was the best with respect to biological activity and toxicity. Its functional derivatives and optically resolved enantiomers were also prepared. Structure-activity relationships are discussed briefly.

Animals↗

PubMed1980

Studies on antihyperlipidemic agents. I. Synthesis and hypolipidemic activities of phenoxyphenyl alkanoic acid derivatives.

The alkanoic acids containing phenoxyphenyl moiety at omega-position were prepared and tested for hypolipidemic property. Some of the compounds showed hypoglycemic activity besides hypolipidemic one. Further study on the selected compound, 3-[4-(4-chlorophenoxy)benzoyl] propionic acid (8) revealed that it increased insulin sensitivity of adipose tissue of obese and diabetic mice (KKAY). The structure-activity relationship was discussed briefly.

Animals↗

PubMed1979