LIsTEN · β-Lactams as flaviviral NS3 protease inhibitors
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-05-02 → 2019-05-31
- EU contribution
- €171,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
β-Lactams as flaviviral NS3 protease inhibitors
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.
Data: CORDIS, © European Union
Project objective
Flaviviral infections already represent a threat to 2.5 billion people living in tropical and sub-tropical regions. As a consequence of climate change and global warming in the near future these infections are expected to spread to areas with moderate climate and the possibility of disease outbreak will exist in Europe, especially around the Mediterranean and Adriatic coast, as well as in the United States of America and large parts of Asia. At the moment no medical treatment against flaviviral diseases is available. Recently, peptide-based compounds which act as flaviviral NS3 protease inhibitors, emerged as potent agents against dengue virus (DENV), Zika virus (ZIKV) and West Nile virus (WNV). These compounds consist of two to four natural or unnatural amino acids and act by binding to the active site of the protease. Accordingly, the incorporation of an electrophilic warhead, a moiety which would facilitate the covalent binding of the inhibitor to the catalytic serine residue, into the peptide inhibitor represents a valuable strategy for the improvement of potency of such inhibitors. The goal of the proposed project is to investigate the potential of β-lactams as electrophilic warheads in DENV, ZIKV and WNV protease inhibitors. For that purpose, new β-lactam derivatives will be synthesized, coupled to peptide inhibitors previously developed by the host group and their affinity to the target will be evaluated by biochemical assays. The most potent compounds will be characterized in more detail and their activity against dengue virus replication in cell culture, off-target binding, membrane permeability and metabolic stability will be studied. We expect the formation of a covalent bond between inhibitor and active site of the enzyme to significantly improve inhibitory activity by increasing binding affinity, as well as to ameliorate selectivity and reduce off-target binding.
Original text from CORDIS.
Participants
- RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG · HeidelbergCoordinatorGermany
Links
Data: CORDIS, © European Union