Biomedical subjects

Judy Halliday

Publications and source records attributed to Judy Halliday.

3 recordsLinked to original sources

PubMed2005

Targeting the forgotten transglycosylases.

Forty years ago, moenomycin was reported as a representative of a novel natural product class with strong antibacterial activity against Gram-positive organisms. Moenomycin was developed as an antimicrobial growth promoter in animal feeds. Mechanistically, moenomycin acts via inhibition of the transglycosylation process at the final stage of the peptidoglycan biosynthesis, in particular through binding directly to the transglycosylase enzymes, thereby preventing polymerisation of lipid II into linear peptidoglycan. Despite moenomycin's success, no developments of direct transglycosylase enzyme inhibitors were reported for over 30 years, probably due to the complexities and uncertainties surrounding the transglycosylation process, in particular the number of enzymes involved in the process and their specific roles. The development of better research tools and an improved understanding of the transglycosylation process, together with the increasing threat presented by multidrug-resistant bacteria, have led to a resurfacing of interest in targeting the forgotten transglycosylases. In addition, several new generation glycopeptides in clinical development inhibit the transglycosylation process, adding further value to the approach. In this paper, we summarise some of the developments in the area of transglycosylase inhibitors over the last 10 years.

Anti-Bacterial Agents↗

PubMed2003

Molecular diversity through sugar scaffolds.

Monosaccharides provide an excellent platform to tailor molecular diversity by appending desired substituents at selected positions around the sugar scaffold. The presence of five functionalized and stereo-controlled centres on the sugar scaffolds gives the chemist plenty of scope to custom design molecules to a pharmacophore model. This review focuses on the peptidomimetic developments in this area, as well as the concept of tailoring structural and functional diversity in a library using carbohydrate scaffolds and how this can lead to increased hit rates and rapid identification of leads, which has promising prospects for drug development.

Animals↗

PubMed2003

Isolation and characterization of a cone snail protease with homology to CRISP proteins of the pathogenesis-related protein superfamily.

The pathogenesis-related (PR) protein superfamily is widely distributed in the animal, plant, and fungal kingdoms and is implicated in human brain tumor growth and plant pathogenesis. The precise biological activity of PR proteins, however, has remained elusive. Here we report the characterization, cloning and structural homology modeling of Tex31 from the venom duct of Conus textile. Tex31 was isolated to >95% purity by activity-guided fractionation using a para-nitroanilide substrate based on the putative cleavage site residues found in the propeptide precursor of conotoxin TxVIA. Tex31 requires four residues including a leucine N-terminal of the cleavage site for efficient substrate processing. The sequence of Tex31 was determined using two degenerate PCR primers designed from N-terminal and tryptic digest Edman sequences. A BLAST search revealed that Tex31 was a member of the PR protein superfamily and most closely related to the CRISP family of mammalian proteins that have a cysteine-rich C-terminal tail. A homology model constructed from two PR proteins revealed that the likely catalytic residues in Tex31 fall within a structurally conserved domain found in PR proteins. Thus, it is possible that other PR proteins may also be substrate-specific proteases.

Amino Acid Sequence↗