Genus Flavivirus comprises more than 70 viruses which are mostly found in tropical and sub-tropical regions. Some flaviviruses, including dengue virus, West Nile virus and Zika virus, can cause infections which represent a serious threat to human health. Although these infections usually result in diseases with mild, flu-like symptoms, in small number of cases severe symptoms can develop that can lead to lethal outcome. Severe symptoms of dengue virus infections include dengue hemorrhagic fever and dengue shock syndrome, West Nile virus can result in severe neurological symptoms, whereas Zika virus infections may cause Guillan-Barre syndrome which leads to microcephaly and deformations in fetuses and newborn children. Dengue and other flaviviruses already represent a threat to 2.5 billion people predominantly in tropical and sub-tropical regions. However, primarily due to global warming this number is expected to increase in near future and people living in moderate climate will be affected as well. Flaviviral diseases, especially West Nile fever, already exist in Europe, especially around the Mediterranean and Adriatic coast. In 2018 over 2000 cases of West Nile virus infection have been reported in Europe. However, more frequent outbreaks are predicted to strike Europe in the future.
Currently, no therapeutics against dengue, West Nile or Zika virus are available on the market and the treatment remains symptomatic. A first dengue vaccine which has been recently released has shown moderate efficacy, whereas the development of chemical agents is still in preclinical stage. Hence, urgent need for drugs against flaviviruses is apparent.
This project was aimed at investigating β-lactams as pharmaceutical agents against flaviviruses, with the focus on dengue and West Nile virus. The target of β-lactam compounds planned in this project was flaviviral NS3 protease. NS3 protease is a valuable pharmacological target as its activity is necessary for virus replication. On the other hand, β-lactams are most well known as very potent antibiotics. Antibacterial activity of β-lactams is based on their ability to inhibit bacterial transpeptidase, an enzyme crucial for the bacterial cell wall synthesis. Due to structural and functional similarities between flaviviral NS3 protease and bacterial transpeptidase, it is reasonable to assume that β-lactams might represent a valuable group of compounds in the development of antiflaviviral drugs. The objective of this project was to investigate β-lactams as inhibitors of NS3 protease and potential antiflaviviral drugs.
