Thomas Shenk

296 million people worldwide are predisposed to developing severe end-stage liver diseases due to chronic hepatitis B virus (HBV) infection. HBV forms covalently closed circular DNA (cccDNA) molecules that persist as episomal DNA in the nucleus of infected hepatocytes and drive viral replication. Occasionally, the HBV genome becomes integrated into host chromosomal DNA, a process that is believed to significantly contribute to circulating HBsAg levels and HCC development. Neither cccDNA accumulation nor expression from integrated HBV DNA are directly targeted by current antiviral treatments. In this study, we investigated the antiviral properties of a newly described allosteric modulator, FLS-359, that targets sirtuin 2 (SIRT2), an NAD+-dependent deacylase. Our results demonstrate that SIRT2 modulation by FLS-359 and by other tool compounds inhibits cccDNA synthesis following de novo infection of …

“I was born in New York on June 30, 1926, and my formative years were spent in a small, gated community named Sea Gate, at the southernmost tip of Brooklyn. By the time I reached junior high school, I had already formed a strong ambition to be a scientist, in part stimulated by my readings about medical scientists:“Arrowsmith” by Sinclair Lewis and “Microbe Hunters” by Paul DeKruif. An inspiring high school “teacher,” Sophie Wolfe, whose job was to supervise the stockroom that supplied the classes in chemistry, physics, and biology, nurtured that ambition. Her love of young people and interest in science led her to start an after-school program of science clubs. Rather than answering questions we asked, she encouraged us to seek solutions for ourselves, which most often turned into mini research projects. Sometimes that involved experiments in the small lab she kept but sometimes it meant going to the library …

The present application provides a method of assaying pyruvate dehydrogenase complex (PDHC) activity in a mammalian cell that expresses human sirtuin 4 (SIRT4) comprising measuring a level of a dihydrolipoyllysine acetyltransferase (DLAT) lipoamide peptide comprising the amino acid sequence TDK [lipoyl] AT in the cell. The present application also demonstrates that sirtuin 4 (SIRT4) acts as a cellular lipoamidase that negatively regulates pyruvate dehydrogenase complex (PDHC) activity through hydrolysis of its lipoamide cofactors.

Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at …

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the …

The present invention relates to compositions comprising isolated, single stranded RNA molecules and pharmaceutically acceptable carriers suitable for injection. The present invention relates to methods for stimulating an immune response and treating tumors. The present invention further relates to kits comprising a cancer vaccine and compositions of the present invention for use as an adjuvant to cancer vaccines.

A method is provided to improve virus production is an infected host cell by culturing the infected cell in an effective amount of alpha-ketoglutarate.

Immunogenic compositions and prophylactic or therapeutic vaccines for use in protecting and treating against human cytomegalovirus (CMV) are disclosed. Subunit vaccines comprising a human CMV protein complex comprising pUL128 or pUL130, and nucleic acid vaccines comprising at least one nucleic acid encoding a CMV protein complex comprising pUL128 or pUL130 are described. Also disclosed are therapeutic antibodies reactive against a CMV protein complex comprising pUL128 or pUL130, as well as methods for screening compounds that inhibit CMV infection of epithelial and endothelial cells, methods for immunizing a subject against CMV infection, methods for determining the capability of neutralizing antibodies to inhibit CMV infection of cell types other than fibroblasts, and methods of diminishing an CMV infection.