Conclusions br Author information The obtained models of com

Conclusions
Author information The obtained models of complexes of FPR2 with most of the described compounds are freely available at the author’s web site: http://www.biomodellab.eu/models/.
Acknowledgements This work was partly done at the Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw. S.F. has received funding from the National Center of Science, Poland, Grant no. 2011/03/B/NZ1/03204. T.M.S and S.F. participate in the European COST Action CM1207 (GLISTEN).
Introduction Influenza is a major public health problem (Kuiken et al., 2012). Annually, influenza epidemics cause 200–500,000 fatal cases worldwide. Viruses of animal origin (mainly avian) can occasionally be transmitted to humans and become pandemic, whose impact can range from mild to severe (40 million deaths for the Spanish Flu). The etiological agents of the disease, the single-stranded RNA influenza viruses, are classified into four types (A, B, C and D). Both influenza A (IAV) and B viruses are responsible for epidemics. IAV are further divided into subtypes based on their surface glycoproteins, hemagglutinin (HA, 18 subtypes) and neuraminidase (NA, 11 subtypes). Current antiviral drugs used for these pathogens are limited to two approved classes of compounds that target viral proteins, thereby promoting selection pressure. The adamantane compounds block the viral M2 ion channel protein, whereas oseltamivir and zanamivir bind the viral enzyme neuraminidase (NA). Particularly regarding adamantanes, a drastic increase in viral resistance has occurred in recent years (Hayden and de Jong, 2011). The substitution of a single amino Methylprednisolone receptor can make a mutant virus resistant without affecting its virulence (Hayden and de Jong, 2011). This illustrates the urgent need for novel antiviral approaches. In this manuscript, to overcome this challenge of resistance, a cellular molecule was targeted instead of the virus. The Formyl Peptide Receptors (FPRs) belong to the G protein-coupled receptors (Le et al., 2002), in which three FPRs with similarities in their amino acid sequences, were described in humans (FPR1, 2 and 3). FPR2 also known as FPRL1 (Formyl Peptide receptor-like 1) or ALX (lipoxin A4 receptor) binds different kinds of ligands: formyl peptides, whose major biological source is bacteria, fatty acid lipid mediators [such as lipoxin A4 (LXA4)] and cellular proteins (such as Annexin-1). FPRs might be important receptors in viral pathogenesis. Indeed, FPR1 is activated by the nonstructural protein 5A of hepatitis C viruses inducing activation and migration of human phagocytes (Lin et al., 2011). Regarding FPR2, it is used by immunodeficiency viruses (IV) as a co-receptor for viral replication (Nedellec et al., 2009) both for human IV-1 isolates (Shimizu et al., 2008a) and simian IV (Shimizu et al., 2008b). In addition, the gp41 and gp120 of HIV-1 activate FPR2 on human phagocytes and monocytes, leading to activation and desensitization of cell immune response, respectively (Deng et al., 1999, Su et al., 1999). More recently, we found that FPR2 has a proviral role during IAV infections and increases virus pathogenesis (Tcherniuk et al., 2016). Inhibiting FPR2-signaling with the FPR2 antagonist WRW4 inhibited IAV replication and protected mice from lethal IAV infections. Altogether, these reports illustrate how FPR2 can be used by several viruses to support their own replication. The aim of this study was to go further into the identification of molecules targeting FPR2 in order to foster the development of FPR2 antagonists as antiviral molecules against influenza. The present report shows that the FPR2 antagonists PBP10 and BOC2 (Ortiz-Munoz et al., 2014, Skovbakke et al., 2015), are two novel potent antiviral inhibitors of both influenza A and B viruses. Thus, FPR2 is a potential tractable target for treating a broad range of influenza viruses.
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