Ileana Cristea and Thomas Shenk: Sirtuin Modulators as Broad Spectrum Antiviral Agents
Invention: Sirtuin Modulators as Broad Spectrum Antiviral Agents
What It Is: Sirtuins are a family of seven proteins that act as enzymes in the body. They control two major epigenetic modifications of proteins and are thought to have a number of roles including the regulation of gene expression. Until recently, much of the work on sirtuins has focused on aging and cancer. But recently Thomas Shenk, professor of molecular biology and the James A. Elkins Jr. Professor in the Life Sciences, together with Ileana Cristea, assistant professor of molecular biology, have discovered that sirtuins have another important function: inhibiting virus replication during infection.
How It Works: To explore the role of sirtuins in viral infection, the researchers conducted a systematic search to see what effect sirtuins have on replication of the human cytomegalovirus (HCMV) in cells. To do this, they looked at what happens to virus growth when sirtuins are “knocked down,” meaning that the activity of individual sirtuin proteins is substantially reduced by molecules which specifically deactivate individual genes.
They found that when they knocked down each of the seven individual sirtuin genes, they saw a drastic increase in viral growth, indicating that the sirtuin genes had been playing a role in suppressing viral replication. This finding suggested that sirtuins were acting as part of the body’s natural antiviral defense, and raised the question of whether molecules that activate sirtuins could be used as antiviral medicines.
Further studies confirmed that the sirtuin enzymes were indeed involved in the cells’ defense against viral infection. The researchers found that virus replication was inhibited when they boosted the activity of certain sirtuins with either small molecule drugs, originally developed as potential cancer treatments, or the naturally occurring plant-based resveratrol, which is found in red wine. The team also found that sirtuins have antiviral properties not just against HCMV but also against other viruses including herpes simplex virus (HSV) and adenovirus. “Based on these studies, sirtuins appear to be a new tool we can use to inhibit virus replication,” said Cristea.
Applications: There is considerable unmet need for therapeutic options to treat viral diseases, so harnessing sirtuins as antiviral drugs could have a significant impact on patient care. Drugs targeting sirtuins have two potential advantages not enjoyed by most of the currently available antiviral drugs. First, since the target is a mechanism that combats the growth of many different viruses, therapeutics that modulate sirtuins will likely have broad spectrum activity, similar to many currently used antibacterial drugs. Second, it is likely to take longer for viruses to develop resistance to sirtuin-specific drugs than is seen for many currently available treatments. This is because many of today’s antiviral drugs kill viruses by attacking virus-coded enzymes, such as proteases. Resistance occurs when the virus mutates and the drug no longer can effectively target the altered viral target. “We anticipate that it will more difficult for the invading virus to accumulate mutations that counteract a cellular defense mechanism,” said Shenk.
Inspiration: This result comes from the integration of quite distinct fields of biology: virology (Shenk) and proteomics (Cristea). “We realized we could harness the power of these different techniques to look at the interplay between viruses and hosts from our different perspectives,” said Cristea, “and that is why it is such a fruitful collaboration.”
Collaborators: This research project is a collaborative effort between Cristea and Shenk along with Emre Koyuncu, a postdoctoral fellow in the Shenk lab, and Yana V. Miteva and Hanna Budayeva, graduate students in the Cristea lab. The work is supported by grants from the National Institute of Allergy and Infectious Diseases and the National Institute on Drug Abuse.
Commercial Status: A provisional patent application has been filed on known sirtuin agonists and several dual antagonists as broad spectrum antiviral therapeutics.