What we work on
Research
We study the chemistry and biology of peptides, from the amyloid oligomers associated with Alzheimer’s disease to antibiotics that kill resistant bacteria.
Amyloid oligomers and Alzheimer's disease
The toxic species in Alzheimer's disease are thought to be small, soluble oligomers of the β-amyloid peptide Aβ. They are transient and heterogeneous, which makes them very hard to study directly.
We get around that by building chemical models. We design macrocyclic β-hairpin peptides derived from Aβ and other amyloidogenic proteins, constrained so that they fold and assemble in a controlled way, and then determine the structures of the oligomers they form.
X-ray crystallography has let us see trimers, tetramers, hexamers, dodecamers and larger assemblies at atomic resolution, and solution-phase NMR shows what happens in water. Current work connects these chemical models to the oligomers found in the brain.
Latest papers
Antibodies, probes and therapies
A structurally defined oligomer mimic is not only a tool for structural biology. It is also an antigen, and that opens a route to antibodies and vaccines aimed at the toxic species rather than at the plaques.
We raise antibodies against our oligomer mimics and ask whether they recognise the pathological forms of Aβ in human brain tissue, and whether they protect neurons from Aβ toxicity. Because the mimic presents a defined conformation, the antibodies it raises are conformation-selective in a way that antibodies raised against the monomer are not.
This work now extends to vaccines and monoclonal antibodies directed at the early, toxic forms of Aβ, and to de novo designed protein binders. The same approach is being applied to other proteins in neurodegeneration, including apolipoprotein E4, tau and TDP-43.
Latest papers
Antibiotics for resistant bacteria
In 2015 we became interested in teixobactin, a newly reported antibiotic against which bacteria struggle to develop resistance, and began working out its chemistry and biology.
By synthesizing analogues and measuring their activity we learned what teixobactin needs in order to kill. X-ray crystallography then showed that it forms dimers and higher-order assemblies through β-sheet formation, and that those assemblies bind its targets on the membrane of Gram-positive bacteria. Fluorescent analogues let us watch the process in living cells.
The work has since widened to clovibactin, the isobactin prodrugs, vancomycin–teixobactin conjugates and other peptide antibiotics. We are using what we have learned to design new antibiotics against MRSA, VRE and other dangerous pathogens.
Latest papers
How we work
The design, synthesis and study of new molecules is central to everything above.
We use small-molecule synthesis, peptide synthesis and protein expression to make the molecules we study, and molecular modeling, NMR spectroscopy and X-ray crystallography to understand their structures and interactions. Experiments with mammalian cells and bacteria, along with fluorescence microscopy, reveal their biological properties, as do some animal studies in mice.
Training and mentorship
Graduate students generate hypotheses, collect and analyse data, and communicate it in both oral and written form. Many mentor undergraduate researchers, which strengthens their own training. James meets with each student individually every week, and works closely with them on drafts when they write for publication.
The group meets on Tuesday afternoons in one of three formats. Research meetings are for presenting and discussing results. Literature meetings cover important papers from the current literature. Workshop meetings give feedback on talks and writing in progress.
Group members are encouraged to present at scientific meetings, among them the Peptide Therapeutics Symposium in San Diego, the Chemistry and Biology of Peptides Gordon Research Conference, the American Peptide Symposium and the meetings of the American Chemical Society.
Joining the group
We welcome enquiries from prospective graduate students, postdoctoral researchers and UC Irvine undergraduates. Write to jsnowick@uci.edu with your CV and a note about what you would like to work on.