Department of Biochemistry and Molecular Biology

Research:

The Shi lab integrates both academic and industrial expertise for basic and translational research. Our research focuses on flaviviruses that cause significant human diseases, such as dengue, Zika, West Nile, and Japanese encephalitis viruses. Despite their global public health burden, there is no clinically approved therapy for flavivirus infection. To address this huge unmet medical need, we take a multidisciplinary approach (i) to study the molecular mechanism of viral replication and (ii) to translate the knowledge into antiviral, vaccine, and diagnostic products. Many of our projects are highly collaborative with both academic and pharmaceutical partners around the world. We also aspire to apply the knowledge achieved from the flavivirus research to drug discovery and vaccine development for other viral pathogens.

1. Flavivirus replication
   Understanding viral replication at a molecular level is essential for development of novel intervention. Our basic research is designed to decipher how viral and cellular factors modulate each other during viral infection, leading to productive viral replication and effective immune response. Our experimental approach includes biochemistry, structural biology, chemical biology, molecular biology, and disease modeling in vivo. The goal of these studies is to define the mechanisms of viral replication and host response that could be used for therapeutics, vaccine, and diagnostic development. Progressing at the forefront of basic research provides a competitive edge for our translational research. In return, the translational research poses new questions and provides unique tools (such as inhibitors) for the viral replication research.
2. Antiviral development
   Four strategies have been pursued to identify flavivirus inhibitors: (i) High-throughput screening (HTS) using viral infection assays; (ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and rational design; (iv) repurposing clinical compounds (that have been previously developed for other indications) for potential treatment of flavivirus infection. New insights derived from viral replication research (described above) have enabled us to design new inhibitors of viral proteins or inhibitors of host factors that are essential for viral infection. Through collaboration with medicinal chemists and pharmacologists, we advance these inhibitors towards preclinical and clinical development.
3. Vaccine development
   We are taking several distinct approaches to develop novel vaccines. (i) We discovered and invented a novel vaccine approach using mutant viruses defective in 2’-O methylation of viral RNA. This vaccine approach is based on our discovery that all flaviviruses encode a viral methyltransferase to methylate N-7 and 2’-O cap of their RNA. The function of 2’-O methylation of viral RNA cap is to mimic cellular mRNA and to evade host innate immune restriction. A cytoplasmic virus defective in 2’-O methylation is replicative; but its viral RNA lacks 2’-O methylation, and is recognized and subsequently eliminated by host immune response, representing a new approach for live-attenuate vaccine development. (ii) Using a 3’UTR deletion approach, we have developed the first live-attenuated Zika virus vaccine candidate that is safe and prevents in utero transmission during pregnancy as well as male reproductive tract infection in animal models. We are advancing this Zika vaccine candidate to clinical trials.
4. Novel diagnosis
   We are taking two approaches to improve flavivirus diagnosis. (i) Antibodies against flaviviral non-structural proteins are more virus-type specific than antibodies against viral structural proteins. This property could be used to develop more specific serological diagnosis. (ii) Plaque reduction assay remains the “gold standard” for flavivirus serological diagnosis. However, plaque assay is labor intensive with low throughput. We are developing stable reporter flaviviruses to replace the traditional plaque assay. These assays will not only improve flavivirus diagnosis in clinics but also facilitate clinical trials of various flavivirus vaccines.