Stanley J. Watowich, PhD
Professor, Department of Biochemistry & Molecular Biology
Tel: (409) 747-4749
Fax: (409) 747-4745
E-mail: watowich@bloch.utmb.edu
Campus Location:623 Basic Science Bldg
Mail Route: 0645
Research
Students and post-docs in my laboratory are (1) studying the structure
and assembly of RNA enveloped viruses, (2) working to discover of novel
drugs and drug targets to combat infectious diseases, and (3)
constructing a quantitative mechanistic model to completely describe
receptor tyrosine kinase activation and signaling. Unifying these
projects is a desire to understand the structural and biophysical
principles that regulate complex biomolecular interactions, and to
predictably modulate those interactions responsible for disease states.
Progress towards these ends is achieved from combining structural,
biochemical, biophysical, genomic, proteomic, and molecular biology
approaches.
1) We have determined the structure of the capsid protein of Venezuelan
equine encephalitis virus (family: Togaviridae) and are characterizing
the structural transitions that occur during the assembly and
disassembly of this enveloped ssRNA virus. The kinetics of virus
assembly are being investigated through the use of a reconstituted in
vitro assembly system. In addition, we are studying the structure,
function, and assembly of the core and envelope proteins from hepatitis C
virus. This integrated information will be used to efficiently screen
combinatorial libraries as part of our structure-based drug design
program to develop agents to inhibit viral assembly and cell-surface
attachment.
(2) Current approaches to developing antipathogen therapeutics are
extremely costly and time-consuming, but rarely successful. To address
this problem, we have implemented a Functional Phenotype screening
technology to rapidly identify novel drug leads and drug targets to
combat infectious pathogens. Using a variety of proprietary cell-based
combinatorial libraries, we have successfully generated independent cell
lines that resist anthrax toxin and all tested alphaviruses. Detailed
differential genomic, proteomic and transgenic analysis of these
discretely modified cells is used to identify and validate critical
antipathogen targets and pathways. When fully deployed, this technology,
together with our new BSL-4 biocontainment laboratories, can be
mobilized to rapidly identify validated drug leads and targets for most
BWT and emerging/reemerging pathogens.
In addition to our holistic Functional Phenotype filtering approach,
we are extending traditional computer-based drug discovery approaches to
identify compounds with antiviral activity in cell culture and animal
models. We use a synergistic combination of high-throughput in vitro and
in silico screening, X-ray crystallography, homology modeling, and
novel bioavailability filters, to identify compounds that effectively
disrupt alphavirus (e.g., Venezuelan equine encephalitis virus) and
flavivirus (e.g., dengue and West Nile viruses) replication in vivo.
(3) We are investigating the conformational and thermodynamic changes
responsible for the activation and signaling of cell-surface receptor
tyrosine kinases (RTKs). For these studies we have developed soluble
molecules that mimic the activated c-MET RTK, a proto-oncoprotein
implicated in tumorogenesis and metastasis. This reconstituted system is
amenable to X-ray crystallographic and biochemical studies.
Significantly, we have measured the thermodynamic and kinetic changes
that accompany receptor oligomerization. This biochemical data has been
incorporated into a detailed quantitative model that explains how
oligomerization facilitates RTK activation and signaling. In addition,
our soluble c-MET RTK is a target for in vitro and computer-based drug
discovery studies that are looking to find inhibitors of receptor
phosphorylation, and thus may serve as anti-metastasis agents.
Publications
Lab Web Page