PRiME Mini Symposium Highlights: U of T Researchers Jump Into Action to Tackle COVID-19
Across the country, the COVID-19 pandemic has rapidly transformed the research landscape. Many laboratories have pivoted their research to support efforts to investigate SARS-CoV-2 biology, demonstrating tremendous flexibility in the face of these new challenges. This crisis has brought forth expertise from diverse disciplines, ranging from microbiology and immunology to biomedical engineering, all with one common goal of fighting COVID-19.
Numerous examples of this exist across the University of Toronto campuses, with some being highlighted recently at the first iteration of the Precision Medicine (PRiME) COVID-19 mini-symposium on May 12th. This virtual gathering comprised of experts in drug discovery, diagnostics, and disease biology featured the research endeavors recently funded by the Toronto COVID-19 Action Fund. This U of T research fund was established to support more than 30 research projects with nearly $9-million in the fight against the novel coronavirus. Research proposals were selected on the basis of their potential to enhance our understanding of this new illness and to develop tools to combat it.
Funded projects include the development of core facilities and open access resources to accelerate research efforts at the U of T and across Canada. Dr. Robert Batey, Chair of the Department of Chemistry, is working with a large assembly of chemists to establish a chemistry core facility to foster collaboration, support commercial chemical needs, provide consulting services, and ultimately assemble a compound screening library as a local resource for drug discovery. Researchers at BioZone and the Structural Genomics Consortium (SGC) founded a Toronto Open Access COVID-19 Protein Manufacturing Center as an open science initiative to provide any Canadian requestor, in business or academia, with high purity SARS-CoV-2 proteins. This team has already developed systems to express and purify 8 of the 25 proteins encoded in the SARS-CoV-2 genome, including numerous non-structural proteins, RNA binding and oligomerization domains of the nucleocapsid protein, and the receptor-binding domain of the spike protein. These resources will be essential for investigation into the basic biochemistry/biology of SARS-CoV-2 and for the development of novel antiviral compounds or neutralizing antibodies.
Researchers are also making headway in the fight against COVID-19 by utilizing their individual expertise to bring new perspectives to antiviral therapeutics. Dr. Masoud Vedadi, a member of the SGC and Assistant Professor in the Department of Pharmacology and Toxicology, is applying years of expertise in histone methyltransferases to tackle COVID-19. SARS-CoV-2 encodes two methyltransferase complexes that are critical for viral RNA cap formation and evasion of the human immune system. The Vedadi lab has proven that methyltransferases are druggable in other systems and may offer a viable approach for the development of antiviral therapies with the potential for activity across diverse coronavirus species. Research in the lab of Dr. Walid Houry, a Professor in the Department of Biochemistry and Chemistry, is studying the ability of SARS-CoV-2 to siege host molecular chaperones during viral replication. The Houry lab aims to take advantage of the large chemical space that surrounds the targeting of molecular chaperones to develop novel antivirals. Dr. Alan Cochrane, a Professor in the Department of Molecular Genetics, is taking a parallel approach to identify novel viral RNA processing inhibitors that disrupt coronavirus replication. Further, the Cochrane lab is generating pseudo-typed lentiviral particles to screen neutralizing antibodies in collaboration with Dr. James Rini and Dr. Sachdev Sidhu.
To identify host dependency factors for SARS-CoV-2 infection and replication, a team led by Jason Moffat, a Professor in the Department of Molecular Genetics, is repurposing their well-established CRISPR screening platform. In this approach, genome-wide knockout pools of human cells are challenged with SARS-CoV-2 to identify genes that are critical for viral replication. This work is being spearheaded by Katie Chan and Furkan Guvenc in the Moffat and Gray-Owen labs, who are on the frontlines of research in the Faculty of Medicine’s Containment Level 3 lab. Basic science investigations such as these are necessary to identify molecular pathways key in SARS-CoV-2 viral infection and to accelerate drug repurposing efforts.
In addition to the developing of therapeutics, the rapid development of diagnostics tests is critical in effectively controlling this ongoing pandemic. Laboratory-based real-time reverse transcriptase polymerase chain reaction-based assays on respiratory samples are the current gold standard for COVID-19 diagnostics. However, numerous alternative testing technologies are being developed that can be de-centralized for remote access outside of testing facilities. Dr. Keith Pardee and his team in the Leslie Dan Faculty of Pharmacy have been working hard to create a “lab-in-a-box” portable testing kit. This system is derived from a low-cost diagnostic platform for the detection of Zika virus which utilizes RNA amplification linked to a toe hold molecular switch to discriminate viral strains at the nucleotide level. Several researchers are working to develop additional point-of-care diagnostics, including paper-based microfluidic biosensors, electrochemical sensors, and structural nucleic-acid nanotechnologies to enable the rapid detection of SARS-CoV-2 and public health intervention.
Serological tests, that look for SARS-CoV-2 specific antibodies in the blood of previously infected individuals, will also be critical to determine how many Canadians have been exposed to the novel coronavirus. Igor Stagljar’s team is developing a blood test that involves flooding the sample with SARS-CoV-2 proteins to promote the binding of specific antiviral antibodies. This test employs a new technology called SIMPL, or split Intein-mediated protein ligation recently published in the journal Nature Communications, that helps increase test sensitivity by strengthening contact between antibodies and their corresponding viral proteins.
These researchers have not only made tremendous strides in combatting COVID-19 but have established long-lasting scientific collaboration and developed essential resources to battle this ongoing threat.
Posted on : 22/05/2020 9:00 AM
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