Washington University School of Medicine
Dr. Patel focused on developing small molecule drugs to treat human papilloma viral (HPV) infections. HPV significantly affects women by increasing the risk of cervical cancer and lung, head and neck cancers. In the lab of Dr. Michael Holtzmann, she conducted high-throughput screens for molecules that modulate interferon signaling. She discovered that certain statins could enhance interferon signaling, and thereby act as an antiviral therapy. She was making excellent progress in her research program, but she chose to leave St. Louis to move to Boston when her husband was offered an academic opportunity. She is currently on maternity leave but plans on continuing her own academic career in the Boston area.
BIRCWH Scholar from 10/01/2013 until 06/02/2014
Statins as therapeutics for HPV infections
Human papillomavirus (HPV) causes significant morbidity and mortality among women. The development of HPV vaccines has therefore been a great advance for women’s heath. However, while these vaccines show protection against their target strains, like most antiviral therapeutic strategies directed at the virus itself, they may prove ineffective against existing and emerging HPV strains that evade vaccine-mediated protection. Thus, there is a need for the development of new therapies for HPV that are broad spectrum, effective forestablished infection, less susceptible to viral resistance, and less expensive so that they are accessible to the most vulnerable populations. In that regard, we have developed a high-throughput screening (HTS) strategy to discover small molecules that enhance the innate host antiviral mechanism through interferon (IFN) signaling. Through our screening efforts, we have identified statins as compounds that enhance IFN signaling as measured by IFN-stimulated response element (ISRE) activity and have confirmed their antiviral properties in cells infected with encephalomyocarditis virus. While statins have been shown to have antiviral properties, their mechanism of action is poorly understood. The statin-induced antiviral effect has been attributed to an HMGCoA reductase (HMGCR)-dependent decrease in prenylation of host proteins necessary for viral replication. But this mechanism does not explain why the reported potencies of statins as antiviral compounds are much lower than their potencies as HMGCR inhibitors, or why certain statins perform better than others in their antiviral capacity with no relationship between HMGCR inhibitory properties and antiviral potency. We hypothesize that statin enhancement of IFN signaling is a novel mechanism that leads to antiviral activity. Herein, we propose to: (1) determine whether statin-induced IFN signal enhancement and anti-HPV activity depends on statin-induced HMGCR inhibition; and (2) define the target/s mediating IFN-dependent statininduced antiviral activity. We expect that the results of these experiments will not only gain better insight into the mechanism of action for statin-induced antiviral activity, but also gain information that we can use to optimize statin structure for the derivation of more potent and efficacious anti-HPV therapeutics in the future. This project may therefore lead to the development of new and more efficacious anti-HPV therapeutics.