Daniel Engel

Engel, Daniel A.

Primary Appointment

Professor, Microbiology, Immunology, and Cancer Biology

Education

  • PhD, Yale University

Contact Information

PO Box 800734
Pinn Hall, 7224
Telephone: 434-924-8633
Fax: 434-982-1071
Email: dae2s@virginia.edu

Research Disciplines

Biochemistry, Biotechnology, Infectious Diseases/Biodefense, Microbiology, Molecular Biology, Molecular Pharmacology, Translational Science

Research Interests

Drug Discovery and Molecular Biology of Pathogenic RNA viruses: Ebola, SARS-CoV-2, Influenza and Zika

Research Description

Drug Discovery and Molecular Biology of Pathogenic RNA viruses: Ebola, SARS-CoV-2, Influenza and Zika

COVID-19, Influenza, Zika fever, and Ebola hemorrhagic fever are diseases caused by highly pathogenic RNA viruses that have proven difficult to target for drug discovery. For influenza, the yearly "seasonal" vaccine does not keep up with the constant genetic drift of the virus, or with new pandemic strains. For Zika virus, there are no vaccines or drugs available. Ebola virus remains unchallenged by pharmaceuticals, and SARS-CoV-2, which causes COVID-19, is new and so far untreatable. We have developed new approaches to identify chemical inhibitors for these viruses. One approach is "chemical-genetic", employing the budding yeast Saccharomyces cerevisiae as a test tube. We genetically modify yeast to express specific viral proteins and then conduct high-throughput screens for new chemical compounds that inhibit the function of the viral protein in the yeast cell. The inhibitors are then tested for their ability to block virus replication in mammalian cell culture. Their mechanisms of action are then studied using a combination of molecular, genetic, medicinal chemistry and structural biology methods. In the case of influenza virus we have targeted two key viral proteins involved in replication and pathogenesis. The NS1 protein normally blocks the host cell's interferon system. Our NS1 inhibitors restore both interferon signaling and the host cell's ability to prevent virus replication. The influenza nucleoprotein NP plays a key role in viral RNA packaging and transcription. Our inhibitors bind directly to NP and cause its mislocalization, thus preventing viral replication. It is hoped that these antiviral compounds will be useful clinically and also as probes of biological function.

Ebola virus also encodes a nucleoprotein, although it is very different from influenza NP. We have solved the structure of the C-terminal domain of Ebola NP and have identified novel functions for this domain in the viral life cycle, including its role in the formation of viral “inclusion bodies”, which are the major site of viral RNA synthesis. We will use this information to design novel drug discovery approaches.

Selected Publications