Pei-Yong Shi, PhD
I. H. Kempner Professor of Human Genetics
Professor, Department of Biochemistry & Molecular Biology
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, 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 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.
- 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 and vaccine 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.
- 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.
- Vaccine development
We discovered and invented a novel vaccine approach using mutant viruses defective in 2’-O methylation of viral RNA. Viruses that replicate in the cytoplasm cannot access the host nuclear capping machinery. These viruses have evolved viral methyltransferase(s) to methylate N-7 and 2’-O cap of their RNA; alternatively, they ‘snatch’ host mRNA cap to form the 5’-end of viral 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. We are applying this novel vaccine approach to flaviviruses.