Department of Biochemistry and Molecular Biology

Research:

The Shi lab integrates academic and industrial expertise for basic and translational research. Our research focuses on viruses that cause significant human diseases, such as dengue, Zika, West Nile, and SARS-CoV-2. 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. 

1. Flavivirus and coronavirus biologyUnderstanding the virus life cycle 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. 
2. Drug discoveryFour strategies are being pursued for antiviral discovery: (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 drugs for treatment of viral infection. Through collaboration with medicinal chemists and pharmacologists, we advance these inhibitors to preclinical and clinical development.
3. Vaccine developmentWe take several approaches for vaccine development: (i) Viruses defective in 2’O methylation as a live-attenuated vaccine; (ii) flavivirus with a 3’UTR deletion as a live-attenuated vaccine; (iii) DNA-launched live-attenuated flavivirus and alphavirus vaccines; (iv) DNA-launched self-amplifying RNA as a universal plug-and-play vaccine platform.  
4. DiagnosisPlaque reduction assay remains the “gold standard” for viral serological diagnosis. This assay is labor intensive and low throughput. We are developing stable reporter flaviviruses, alphaviruses, and coronaviruses to replace the traditional plaque assay. These new assays will not only improve serological diagnosis but also facilitate drug discovery and vaccine evaluation.

5. Biography: Pei-Yong Shi is John Sealy Distinguished Chair in Innovations in Molecular Biology at University of Texas Medical Branch (UTMB). He is an elected Fellow of American Academy of Microbiology, adjunct Professor of Emerging Infectious Diseases at the Duke-NUS Graduate Medical School in Singapore, and Honorary Professor at the Wuhan Institute of Virology, Chinese Academy of Sciences. He works on RNA virus, drug discovery, and vaccine research. His unique expertise in public health laboratory (York State Department of Health), pharmaceutical companies (Novartis and Bristol-Myers Squibb), and academia (UTMB and Yale) allows him to work on both basic and translational research. He has published >300 peer-reviewed papers. His group developed the first reverse genetic systems for the epidemic West Nile virus and Zika virus and discovered flavivirus N7 and 2’O methyltransferase activities. His team also published the first peer-reviewed infectious clone and reporter virus for SARS-CoV-2. Besides academic excellence, he also has a stellar track record of senior leadership role at major pharmaceutical companies (e.g., Executive Director at Novartis Institute for Tropical Diseases) where he set up antiviral strategies and executed drug discovery and development. He contributed to the development of Fostemsavir, an FDA-approved HIV drug. Many of his technologies have been licensed to leading pharmaceutical companies for countermeasure development. A recent example is his reporter neutralization assay that has enabled the rapid development of Pfizer’s COVID-19 vaccine, the first vaccine with 95% efficacy in humans. 

   Representative recent publications

1. Liu et al. 2021. Neutralizing Activity of BNT162b2-Elicited Serum. N. Engl. J. Med. doi: 10.1056/NEJMc2102017.
2. Zhang et al. 2021. A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence. Cell, https://doi.org/10.1016/j.cell.2021.02.044.
3. Xie, et al. 2021.Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. Nat. Med. doi: 10.1038/s41591-021-01270-4
4. Chen et al. 2021. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat. Med. doi: 10.1038/s41591-021-01294-w.
5. Moquin et al. 2021. NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models. Sci. Transl. Med. doi: 10.1126/scitranslmed.abb2181.
6. Vogel et al., 2021. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature. doi: 10.1038/s41586-021-03275-y.
7. Xie et al. 2021. Engineering SARS-CoV-2 using a reverse genetic system. Nat. Protoc. doi: 10.1038/s41596-021-00491-8
8. Plante et al. 2020. Spike mutation D614G alters SARS-CoV-2 fitness. Nature. doi: 10.1038/s41586-020-2895-3.
9. Walsh et al. 2020. Safety and Immunogenicity of two RNA-Based COVID-19 Vaccine Candidates. NEJM. doi: 10.1056/NEJMoa2027906.
10. Xie et al. 2020. A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19. Nature Commun. 11(1):5214.
11. Mulligan et al. 2020. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 586(7830):589-593.
12. Sahin et al. 2020. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T-cell responses. Nature. 586(7830):594-599.
13. Xia et al. 2020. Evasion of type-I interferon by SARS-CoV-2. Cell Rep. 33(1):108234.
14. Xia et al. 2020. A cocrystal structure of dengue capsid protein in complex of inhibitor. PNAS. 117(30):17992-18001.
15. Shan et al. 2020. A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission. PNAS. 117(33):20190-20197.
16. Giraldo et al. 2020. Envelope Protein Ubiquitination Drives Zika Virus Entry and Pathogenesis. Nature. 585(7825):414-419.
17. Muruato et al. 2020. A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation. Nature Commun. 11(1):4059.
18. Baker et al. 2020. Using recombination-dependent lethal mutations to stabilize reporter flaviviruses for rapid serodiagnosis and drug discovery. EBioMedicine. 57:102838.
19. Xie et al. 2020. An Infectious cDNA Clone of SARS-CoV-2. Cell Host Microbe. 27(5):841-848.e3.