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Checco J.W.,University of Wisconsin - Madison | Lee E.F.,Walter and Eliza Hall Institute of Medical Research | Lee E.F.,University of Melbourne | Lee E.F.,La Trobe University | And 18 more authors.
Journal of the American Chemical Society | Year: 2015

Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-α-amino acids) suffer from significant limitations in vivo. Short half-lives due to rapid proteolytic degradation and an inability to cross cell membranes often preclude biological applications of peptides. Oligomers that contain both α- and β-amino acid residues ("α/β-peptides") manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous "α-peptides". This report documents an extension of the α/β-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated α/β-peptides based on a "stapled" Bim BH3 α-peptide, which contains a hydrocarbon cross-link to enhance α-helix stability. We show that a stapled α/β-peptide can structurally and functionally mimic the parent stapled α-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the α/β-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled α-peptide. These results show that backbone modification, a strategy that has received relatively little attention in terms of peptide engineering for biomedical applications, can be combined with more commonly deployed peripheral modifications such as side chain cross-linking to produce synergistic benefits. © 2015 American Chemical Society.

Dyson Z.A.,La Trobe Institute of Molecular science | Tucci J.,La Trobe Institute of Molecular science | Seviour R.J.,La Trobe University | Petrovski S.,La Trobe University
PLoS ONE | Year: 2015

Nine bacteriophages (phages) infective for members of the genus Gordonia were isolated from wastewater and other natural water environments using standard enrichment techniques. The majority were broad host range phages targeting more than one Gordonia species. When their genomes were sequenced, they all emerged as double stranded DNA Siphoviridae phages, ranging from 17,562 to 103,424 bp in size, and containing between 27 and 127 genes, many of which were detailed for the first time. Many of these phage genomes diverged from the expected modular genome architecture of other characterized Siphoviridae phages and contained unusual lysis gene arrangements. Whole genome sequencing also revealed that infection with lytic phages does not appear to prevent spontaneous prophage induction in Gordonia malaquae lysogen strain BEN700. TEM sample preparation techniques were developed to view both attachment and replication stages of phage infection. Copyright: © 2015 Dyson et al.

Dyson Z.A.,La Trobe Institute of Molecular science | Tucci J.,La Trobe Institute of Molecular science | Seviour R.J.,La Trobe University | Petrovski S.,La Trobe University
Applied and Environmental Microbiology | Year: 2015

Three Tsukamurella phages, TIN2, TIN3, and TIN4, were isolated from activated sludge treatment plants located in Victoria, Australia, using conventional enrichment techniques. Illumina and 454 whole-genome sequencing of these Siphoviridae viruses revealed that they had similar genome sequences, ranging in size between 76,268 bp and 76,964 bp. All three phages shared 74% nucleotide sequence identity to the previously described Gordonia phage GTE7. Genome sequencing suggested that phage TIN3 had suffered a mutation in one of its lysis genes compared to the sequence of phage TIN4, to which it is genetically very similar. Mass spectroscopy data showed the unusual presence of a virion structural gene in the DNA replication module of phage TIN4, disrupting the characteristic modular genome architecture of Siphoviridae phages. All three phages appeared highly virulent on strains of Tsukamurella inchonensis and Tsukamurella paurometabola. © 2015, American Society for Microbiology.

Aprile A.,La Trobe Institute of Molecular science | Wilson D.D.J.,La Trobe Institute of Molecular science | Richards A.F.,La Trobe Institute of Molecular science
Dalton Transactions | Year: 2012

The coordination preferences of the tetradentate Schiff base, N,N′-ethylenebis(acetylacetoimine), H 2L, with a variety of group 13 precursors, led to the formation of a series of mono and binuclear products. The reaction of H 2L with AlMe 3 and Me 2GaCl afforded the binuclear complexes, [L{Al(Me) 2} 2] 1 and [H 2L{GaCl(Me) 2} 2], 3, the latter an adduct of the neutral ligand. Treatment of 1 with iodine generated the cationic Al(iii) complex, [LAl(thf) 2]I, 2, while the addition of n-BuLi to H 2L, followed by reaction with GaCl 3 and InCl 3 led to an ionic complex [{LGaCl} 2(μLi)]GaCl 4, 4, an In(iii) dimer, [LInCl] 2, 5 and monomeric [LInCl(thf)], 6. In contrast, the reaction of [In{N(SiMe 3) 2} 3] with H 2L yielded a homoleptic, air stable, indium complex, [L 3In 2], 7. All products were definitively characterized by X-ray crystallography and their structures confirmed by pertinent spectroscopic techniques. © 2012 The Royal Society of Chemistry.

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