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Viral protein/nucleic acid interactions within the host cell
Viral protein/nucleic acid interactions within the host cell
Proteins (A) and small molecules (B) can interact with G-quadruplexes; capitalizing on key features will enhance selectivity of the agents designed/created.
Targeting the chronic form of Hepatitis B Virus - the cccDNA
Targeting the chronic form of Hepatitis B Virus - the cccDNA
Covalently closed circular DNA (cccDNA) hides in the nuclei of infected cells and produces all the transcripts needed for HBV replication. Our current drugs only directly target processes downstream of cccDNA, so if we want to tackle chronic HBV, we first have to find and bind to this form.
We're using structural methods to study the interaction of a host protein with a key site in HBV's cccDNA where it forms a unique DNA structure, a G-quadruplex. Once we know how the host protein attaches, we can determine ways to create a mimetic to bind in a similar way.
Understanding the role of HBx in hepatocellular carcinoma (HCC)
Understanding the role of HBx in hepatocellular carcinoma (HCC)
Some high-risk HBV mutations can increase the chances of hepatocellular carcinoma (HCC) development. These mutations may manifest in the HBx protein - a small multifunctional protein produced by HBV. Here, we're looking at how different mutations influence viral activity and protein binding partners.
Schematic of the HBx protein (upper) and Alphafold3 predicted model of HBx (lower).
Pregenomic RNA fate. pgRNA is processed to make either a circular or linear viral form. Linear forms are at highest risk of integration.
Improving prognostication models for HCC: examining precursors to integrative cancers.
Improving prognostication models for HCC: examining precursors to integrative cancers.
When HBV replicates, it uses an RNA form (pre-genomic RNA, pgRNA) as the intermediate step. Normally, that pgRNA is converted to the circular form that makes up the infectious virion; sometimes it makes a mistake during the process that leads to a linear form. The linear forms are the ones which can integrate into host DNA and occasionally lead to cancer. Understanding the processes involved will help us predict who may be at greatest risk.
Studying the interaction of Hepatitis D proteins with Hepatitis B
Studying the interaction of Hepatitis D proteins with Hepatitis B
HDV is a deficient virus that needs HBV's surface proteins in order to complete its replication cycle. When seen clinically in co-infection, HBV levels are decreased - suppressed by HDV. This project looks at HDV proteins' interaction with HBV RNA to study how it interacts at the molecular level.
Biophysical study of key physiological interactions
Biophysical study of key physiological interactions
PDB from Ladame, et al, 2006; figure adapted from Meier-Stephenson, 2022
Zinc Finger protein interactions with G-quadruplexes
Zinc Finger protein interactions with G-quadruplexes
Zinc finger proteins (ZFPs) serve a diverse range of functions in the cell, including DNA recognition and transcriptional activation. ZFPs are also known to bind G-quadruplexes, however there is limited high-resolution data on how this occurs and how this is made selective. This work aims to study the interaction of several ZFPs (Sp1, YY1, MAZ) with promoter-region G-quadruplexes they are known to bind (i.e., c-kit, HRAS, VEGF). Studying and comparing how these interact at the molecular level will provide insights into this class of proteins that play such critical roles in the cell and may provide the template for creating drugs to selectively interfere with these processes.
Translational projects - Global Health
Translational projects - Global Health
Sequencing - protein production/purification - biophysical studies. Application of skill sets to broader global health questions:
Molecular Epidemiology of HBV
Molecular Epidemiology of HBV
Partners in Mauritania - Knowing the prevalence of clinically-relevant HBV mutations in a population can help inform public health programing.
Point-of-Care Diagnostics
Point-of-Care Diagnostics
At the simplest level, creating a diagnostic test requires a bait and a target...
Emerging pathogens
Emerging pathogens
Serosurveillance can be a powerful tool to monitor trends of infectious pathogens overtime.
A Multidisciplinary Team
Our team combines are range of areas of expertise from computational chemistry to biophysics to biochemistry to virology to medicine. Working in a setting where all stages of the discovery process are present and interacting will give a broad scope of the project(s) being worked on.
Collaborators
Here are some of the incredible researchers our team collaborates with:
Dr. Lorne Tyrrell, Distinguished Professor, Dept MMI and Director of Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB
Dr. Kristi Baker, Associate Professor, Division of Oncology, Dept of Medicine, University of Alberta, Edmonton, AB
Dr. David Marchant, Associate Professor, Dept MMI, University of Alberta, Edmonton, AB
Dr. Trushar Patel, Associate Professor, Dept Biochemistry and Chemistry, University of Lethbridge, Lethbridge, AB
Dr. Carla Coffin, Professor and Director of the Calgary Liver Unit, Dept of Medicine, University of Calgary, Calgary, AB
Dr. Jordan Feld, Professor, Dept of Medicine, University of Toronto, Toronto, ON
Dr. Jason Kindrachuk, Professor, University of Manitoba, Winnipeg, MB
The Canadian Hepatitis B Network - and its members
The Canadian Biobank Alliance - Director Dr. Angela Crawley
Always open to potential collaborations! - please reach out (meierste@ualberta.ca)
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