Antiviral Drug Discovery Targeting Zika Virus Protease
Abstract
This project addresses the Topic Area of “Emerging Infectious Diseases,” focusing on the Area of Encouragement in “Evaluation of non-vaccine prophylactics or therapeutics to prevent/treat dengue or Zika virus disease.” Zika virus (ZIKV) belongs to the genus Flavivirus of the virus family Flaviviridae, which includes other important human pathogenic viruses such as yellow fever, dengue (DENV), and West Nile viruses. These viruses are transmitted among humans through mosquitos. From its discovery in 1947 in Uganda, Africa to the mid 2000s, ZIKV was found to cause only sporadic Zika fever in humans with flu-like, self-healing symptoms in Africa and Asia, which caused little attention to the medical and scientific communities as well as the public. ZIKV caused three major outbreaks in the Yap Island in the west Pacific Ocean (2007), French Polynesia in the central Pacific Ocean (2013), and Brazil (2015), in which >1,000,000 ZIKV infections were reported and many patients sought medical treatment or hospitalization. More seriously, ZIKV infection causes a 20-fold increase in the incidence of serious diseases of central and peripheral nervous systems (CNS and PNS), such as microcephaly (small brain/head) of newborns and Guillain-Barre syndrome (showing widespread muscle weakness, pain, and even paralysis and breath failure). A recent Centers for Disease Control and Prevention (CDC) study disclosed that CNS birth defects occur in a rate of ~0.3% in the pre-ZIKV era of 2013-14. However, a 6% defect rate (26 infants/fetuses out of 442) was observed in 2016 for women with ZIKV infection during pregnancy in the US. Since 2015, ZIKV has quickly spread across Latin Americas and the southern US (e.g., Florida and Texas). The World Health Organization has announced ZIKV is a “Public Health Emergency of International Concern.” Moreover, the CDC has declared ZIKV can be transmitted through sex or body fluids even when infected people have no symptoms. Therefore, ZIKV could become endemic in the tropical and subtropical regions worldwide and cause catastrophic consequences to the public health. However, except for mosquito control, there have been no antiviral drugs or vaccines for the prevention and treatment of ZIKV infection. Zika virus protease (ZVpro) is a viral protein that is essential for viral replication. ZVpro is therefore a drug target for ZIKV infection. The overall objectives of this proposal are to use a combination of rational inhibitor design, medicinal chemistry, X-ray crystallography, and biological activity testing to discover and develop potent and selective small-molecule inhibitors of ZVpro. The goal is to identify several drug candidates having strong anti-ZIKV activities in cellular assays and mouse models. Success of this project would lead to finding of the first drug candidates that possess potent activity to prevent ZIKV replication in human cells as well as in mice. These compounds will be available to other scientists and could be useful chemical probes for virology, immunology, and pathology studies of ZIKV. The ultimate goal and long-term impact of the project is that these compounds may be further developed to be clinically useful drugs to prevent and treat ZIKV infections. Given the quick and widespread presence of ZIKV in the tropical and subtropical areas worldwide as well as dual (mosquito and sex/body fluid) transmission routes for ZIKV, this research is of high importance to the public health. Moreover, the US military has deployed in a number of countries with risk of ZIKV. In August 2016, the Department of Defense announced that 41 military members and 7 family members were infected with ZIKV, including 1 pregnant woman. The number of infected military members and their families is expected to increase during the past year and in the future. Therefore, this project has a high relevance to the healthcare needs of the US military.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810368
Entities
People
- Yongcheng Song
Organizations
- Baylor College of Medicine
- United States Army