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Biomedical subjects

Gabriela Mustata

Publications and source records attributed to Gabriela Mustata.

4 recordsLinked to original sources

Approaches to oral drug delivery for challenging molecules.

Advances in biotechnology, high throughput screening and computational chemistry have led to a considerable increase in the number of protein and peptide therapeutics and other macromolecular drugs. Working with macromolecules, however, poses a number of challenges that must be overcome to successfully develop these compounds into safe and effective therapeutics. Significant efforts in pharmaceutical and academic laboratories have been expended in finding ways to deliver macromolecular drug molecules by the oral route, which can significantly improve patient compliance, convenience, and efficacy. Nevertheless, for a drug molecule to be orally bioavailable, it has to overcome the natural physiological processes of breaking down molecules in the gastrointestinal tract, and to traverse a relatively impermeable epithelial layer of cells that line the gastrointestinal tract. This article provides a summary of the challenges that researchers need to surmount in the development of orally absorbable peptide and protein drugs, and gives an overview of the novel approaches currently in progress in the field of oral delivery.

Administration, Oral↗

Drug delivery global summit--evaluating emerging technologies.

Two day-long sessions at the Drug delivery global summit, organised by SMi Group Ltd, were devoted to discussion on critical aspects of drug delivery, including advances in drug delivery systems and their applications to new products, with a primary focus on oral systems, but also highlighting recent progress in inhalation, parenteral and transdermal delivery. The event included case studies from big pharma, biotech and drug delivery companies to illustrate emerging delivery technologies and how they can be applied to develop innovative products. The conference created a platform for discussion on a range of topics from scientific issues and challenges to ways of establishing mutually beneficial relationships between technology and pharma companies.

Chemistry, Pharmaceutical↗

Cluster analysis of water molecules in alanine racemase and their putative structural role.

Conservation of water molecules was identified by a cluster analysis of seven crystal structures of alanine racemase from Bacillus stearothermophilus. A total of 47 clusters of consensus water sites were determined and found to be highly localized, as indicated by their low mobilities. These clusters are located in the region of the active sites as well as at the interface between the N-terminal domain (the alpha/beta-barrel) of the first monomer and the C-terminal domain of the second monomer. The clusters located at the dimer interface form extensive hydrogen-bonding networks linked to the protein backbone. These water-mediated hydrogen bonds, and also all hydrogen-bonding interactions at the dimer interface, were monitored during a 2 ns molecular dynamics simulation and showed that when the inhibitor propionate was bound to the enzyme, some of these interactions were disrupted. The data we present here indicate that the consensus water sites identified at the interface between the two monomers of alanine racemase may play a structural role, which is to maintain and stabilize the alanine racemase dimer. A second role might be to supply the active site continuously with water molecules in order to allow rapid equilibration of active site protons with the solvent.

Alanine↗

The crystal structure of Trichomonas vaginalis ferredoxin provides insight into metronidazole activation.

Crystallographic studies revealing the three-dimensional structure of the oxidized form of the [2Fe-2S] ferredoxin from Trichomonas vaginalis (TvFd) are presented. TvFd, a member of the hydrogenosomal class of ferredoxins, possesses a unique combination of redox and spectroscopic properties, and is believed to be the biological molecule that activates the drug metronidazole reductively in the treatment of trichomoniasis. It is the first hydrogenosomal ferredoxin to have its structure determined. The structure of TvFd reveals a monomeric, 93 residue protein with a fold similar to that of other known [2Fe-2S] ferredoxins. It contains nine hydrogen bonds to the sulfur atoms of the cluster, which is more than the number predicted on the basis of the spectroscopic data. The TvFd structure contains a large dipole moment like adrenodoxin, and appears to have a similar interaction domain. Our analysis demonstrates that TvFd has a unique cavity near the iron-sulfur cluster that exposes one of the inorganic sulfur atoms of the cluster to solvent. This cavity is not seen in any other [2Fe-2S] ferredoxin with known structure, and is hypothesized to be responsible for the high rate of metronidazole reduction by TvFd.

Animals↗