The influenza A virus is a contagious and severe respiratory infection that affects animals but also humans. Researchers from the University of Barcelona (UB) have synthetized some molecules which are able to block the virus that causes influenza A and some of the mutations that make it resistant to common drugs.
The team led by Santiago Vázquez, researcher at the Laboratory of Medicinal Chemistry, and the team headed by F. Javier Luque, from the Department of Physicochemistry, both from the Faculty of Pharmacy and the Institute of Biomedicine of UB (IBUB), participated in the study, published in the Journal of Medicinal Chemistry, of the American Chemical Society. The teams led by Lieve Naesens (Rega Institute, Leuven, Belgium), Robert A. Lamb and Lawrence H. Pinto (Northwestern University, Illinois, USA) and William F. DeGrado (University of California, San Francisco, USA) collaborated in the study too.
A new compound with particular structure
The study of these anti-viral molecules emerged from the research developed by Matías Rey Carrizo and Marta Barniol Xicota, PhD students at UB and members of the group led by Santiago Vázquez. The study was published on the prestigious scientific journal Angewandte Chemie. Researchers have developed a compound that has an uncommon structure with four cyclohexane rings in a “boat” conformation, instead of the commonly encountered “chair” conformation. According to Santiago Vázquez, “the ‘boat’ conformation has much more energy and it is a transition state”. “To achieve it – he adds – we used a hydrocarbon that includes a carbon-carbon double bond which, contrary to what it could be thought, it is extremely tense but not plain”. The structure of this compound was determined by Mercè Font-Bardia, from the X-Ray Diffraction Unit of the Scientific and Technological Centers of UB (CCiTUB), who also signs the scientific paper.
Results are very interesting from a theoretical point of view. Moreover, the team led by Santiago Vázquez has adequately modified the polycyclic structure to prepare compounds with high antiviral activity, including against several drug-resistant mutants of influenza A virus.
Effective against influenza virus and its mutant forms
Amantadine and rimantadine have been in clinical use as anti-influenza virus agents for decades. Their mechanism of action is based on the inhibition of the M2 proton channel of the influenza A virus, essential to viral infection and replication. However, the efficacy of these two drugs dropped sharply in recent years due to the global distribution of mutant viruses carrying drug resistance. “The compounds we synthetized are, to date, some of the most powerful ones against V27A and L26F M2 mutants of the influenza A virus, and resistant to amantadine and rimantadine. In addittion, the new compounds keep the activity against the wild-type strain of the virus”, explains Professor Santiago Vázquez.
The international collaboration that has achieved to synthetize these new compounds will continue in order to design, synthetize and pharmacologically evaluate new active compounds against other virus strain. The research has just received the support given by a PRACE project. That means it will have access to the supercomputing resources given by the supercomputer Marenostrum in the Barcelona Supercomputer Center (BSC). Furthermore, results may encourage other research groups to use the M2 channel of influenza virus as therapeutic target against the influenza A virus.
The World Health Organization (WHO) calculates that influenza occurs globally with an annual attack rate estimated at 5%-10% in adults and 20%-30% in children. Illnesses can result in hospitalization and death mainly among high-risk groups (the very young, elderly or chronically ill). Worldwide, these annual epidemics are estimated to result in about 3 to 5 million cases of severe illness, and about 250,000 to 500,000 deaths.
Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus, Rey-Carrizo M1, Barniol-Xicota M, Ma C, Frigolé-Vivas M, Torres E, Naesens L, Llabrés S, Juárez-Jiménez J, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S., Journal of Medicinal Chemistry, doi: 10.1021/jm5005804, published 18 June 2014.
Dimerization of Pyramidalized 3,4,8,9-Tetramethyltetracyclo [4.4.0.03,9.04,8]dec-1(6)-ene to a Hydrocarbon Featuring Four Cyclohexane Rings in Boat Conformations, Matias Rey-Carrizo, Marta Barniol-Xicota, MercÈ Font-Bardia, and Santiago Vázquez., Angewandte Chemie. DOI: 10.1002/ange.201403985, published online 16 June 2014.
Source: University of Barcelona