The goals of the Zhang lab include answering basic biological
questions, developing novel biotechnologies, and identifying new drug
therapies. We utilize both classic and novel techniques in the fields
of biochemistry, enzymology, molecular biology, protein chemistry,
organic chemistry, and many other biophysical techniques. We are
currently working on the following two major types of research:
1. Development of New Drug targets: Gram-positive
bacteria are the cause of many serious human diseases. Recently,
drug-resistant bacteria, such as community-acquired
methicillin-resistant Staphylococcus aureus, have been marching across the U.S at alarming pace, Like other gram-positive bacteria, Staphylococcus aureus
infect host cells through virulence factors anchored on their cell
walls by the enzyme sortase A. Thus, compounds that can disrupt sortase
A activity may function as a new class of antibiotics. My lab has
recently discovered that sortase A is a dimeric protein both in vitro and in vivo.
We have also shown that dimerization plays an important role in the
activity of sortase A. Based on this new mechanism, we will isolate
small molecule(s) as capable of disrupting dimerization of sortase A by
screening a library containing 60,000 different compounds using a
cell-based, high throughput assay. These isolated compounds may serve
as drug candidates for antimicrobial infections.
2. Biotechnology development: We
are interested in creating novel biomacromolecules with tailored
physical and chemical properties by combining the tools and principles
of chemistry and biology. These molecules will then be applied to the
study and manipulation of signaling pathways. Currently we are working
on the following projects:
a. Research tools in mammalian cells: Site specific in vivo cross-linking method to isolate ligands for orphanage oGPCR; mammalian two-hybrid system.
b. Synthetic Engineering: We would like to develop a "protein cloning" technology to create protein analogues with non-polyamide backbones both in vitro and in vivo. With this technology, we would like to:
1) Create “biobarcodes” for various proteins with distinctive DNA/PNA
sequences, 2) Site-specifically insert "switch box" moieties into the
backbone of a protein of interest to control protein conformation with
light or temperature.
c. Biological Pathway Engineering (Cell surgery):
We are also interested in doing engineering at whole cell level. As a
starting point, we would like to switch a cytokine-regulated JAK-STAT
signal-transduction pathway to a light/temperature-regulated signaling
pathway. We believe that such research can provide a powerful platform
to study the kinetics and thermodynamics of a signaling pathway of
interest.
d. Reverse protein engineering: Before
the protein world, I believe there is a peptide world. Our hypothesis
is that peptides can be created that can mimic the functions of larger
proteins, at least to a certain degree. This peptide could then serve
as a template for further modification and enhancement using organic
chemistry. To test this notion, my lab is developing peptidic GFP
molecule.
