Nominated Principal Applicant
François Jean, University of British Columbia
Principal Applicants
Mel Krajden, University of British Columbia
Ivan Robert Nabi, University of British Columbia,
Natalie Prystajecky, University of British Columbia
Theodore Steiner, University of British Columbia
Wayne Vogl, University of British Columbia
Co-Applicant
Andrea Olmstead, University of British Columbia
Objectives
As variants of concern (VOCs) have the potential to spread more quickly, resist therapeutics, escape vaccine-induced immunity, and/or cause more severe disease, this research aimed to understand their biological properties (i.e., mutation rate, infectivity, and pathogenesis) and how they respond to medical countermeasures such as antiviral therapeutics.
This project therefore developed systematic strategies to evaluate various aspects of SARS-CoV-2 infection associated with VOCs and assessed potential therapeutics in cell-based systems, e.g., plaque assays and high-throughput bioimaging (Shapira et al., 2022). These assays offered a quick and convenient methodology for assessing the infectivity and spread of SARS-CoV-2 VOC as well as their susceptibility to therapeutics (Shapira et al., 2022 and Saberian et al., 2022).
To accomplish the above objectives, in early 2020, Dr. François Jean, a molecular virology expert in coronaviruses and other RNA viruses (i.e., Zika, dengue, hepatitis C viruses), rapidly redirected resources to characterize the molecular biology of and investigate therapeutic strategies against SARS-CoV-2.
By leveraging a partnership between UBC (Dr. Jean; Founder of UBC FINDER) and the BC Centre for Disease Control (BCCDC: Dr. Krajden; Medical Microbiologist) and funded by CoVaRR-Net, this research accelerated the availability and use of high-quality/real-time evidence to support Canada’s ongoing response to the pandemic to better prevent, detect, treat and manage COVID-19, and established SARS-COV-2 VOC sharing between the two BC CL3 facilities (BCCDC and FINDER).
Major Successes
General
- This research enhanced provincial collaborative efforts (UBC, BCCDC) to mitigate the rapid spread of COVID-19 and related negative consequences by forging a multidisciplinary response team to understand the phenotypic consequences and therapeutic susceptibility of emerging variants of concern.
- The results of this Year 1 project led to establishing Pillar 10 within CoVaRR-Net in Year 2, with Dr. Jean as Pillar Lead.
- This project garnered two publications in very high-impact journals, one being the first very high impact VOC publication for CoVaRR-Net: Shapira et al., 2022 and Saberian et al., 2022.
Scientific
- Reported N-0385 as a novel potent small-molecule protease inhibitor of human TMPRSS2 and as the first SARS-CoV-2 pan-variant host-directed antiviral (HDA) effective in vivo against the Delta B.1.617.2 VOC. N-0385 provided nanomolar potency against SARS-CoV-2 infection in human cells and patient-derived colon organoids without detectable toxicity. Furthermore, in the K18-hACE2 mouse model, early N-0385 treatment resulted in complete protection against COV B.1.617.2 mortality—suggesting a novel treatment option against emerging VOC.
- DEEMD identified known SARS-CoV-2 inhibitors, such as remdesivir and aloxistatin, supporting the validity of this approach. DEEMD can be deployed for other emerging viruses and datasets to rapidly identify future candidate antiviral treatments.
Budget
CoVaRR-Net is funding this research, which was first proposed to the Canadian Institutes of Health Research’s (CIHR) Emerging COVID-19 Research Gaps and Priorities – Variants funding call, with a $349,500 cash contribution.