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  • Regarding IAV types of hemagglutinin and types of neuraminid


    Regarding IAV, 18 types of hemagglutinin and 11 types of neuraminidase were described and none of the commercialized antiviral drugs are susceptible to protect against all strains that will emerge from the animal reservoir (Webby and Webster, 2003). The strong dependencies of influenza viruses on well known specific cellular functions appear particularly relevant for the development of universal antivirals. As shown here, antagonists of FPR2 inhibited replication of several strains of influenza A and B viruses. FPR2 antagonists act through a delay in ERK activation, a signaling pathway required for endosomal acidification and viral-endosomal fusion (Marjuki et al., 2011), viral ribonucleoprotein (vRNP) translocation from the nucleus to the L-161,982 and viral replication (Droebner et al., 2011, Pleschka et al., 2001). Thus, FPR2 inhibitors might impair different steps of the virus cell cycle. Also, since the acidification of the endosome and vRNP translocation is required for all strains of influenza virus life cycle, FPR2 should most likely protect against any novel influenza strain that could emerge from the animal reservoir and cause a pandemic.
    Acknowledgements This work was supported by the ANR (ANR-13-BSV3-0011), Fondation de France (Grant 00066467), Fondation Vaincre la mucoviscidose and Association Gregory Lemarchal (Grant N°RF20160501641) and SATT Sud-Est (789-SA-16-UAM). Authors are grateful to Elodie Dormes and Florence Alesandrini for helpful advices. We thank Bekendam Roelof and Remy Collier for reading the manuscript regarding english grammar corrections. We thank A. Harmache (INRA, Nouzilly, France) for advice regarding vRNA QRT-PCR experiments. A patent has been filed on the role of FPR2 antagonists against influenza viruses by Beatrice Riteau and Marie-Christine Alessi.
    Introduction Forty years ago, Schiffmann et al. [1] reported that N-formylated peptides are potent chemotactic agents for human neutrophils. Further study of the biological targets of formylated peptides led to the identification and subsequent cloning of human formyl peptide receptor 1 (FPR1) [2], [3]. Two other relatively conserved low-affinity fMLF receptors, now termed as FPR2 and FPR3, were subsequently cloned (reviewed in [4]). FPR1 is a key regulator of the inflammatory environment. However, the expression of FPRs in various nonphagocytic cells suggests that these receptors also participate in functions other than innate immunity and may represent unique targets for therapeutic drug design [5], [6], [7]. Such drugs may have the potential to treat many inflammatory diseases, including rheumatoid arthritis, asthma, other auto-immune diseases, and stimulate wound healing [6], [8], [9], [10]. Since FPRs represent potentially important therapeutic targets, much attention has been focused over the last two decades on the identification of natural and synthetic compounds that interact with these receptors and/or interfere with FPR-dependent pathways. To date, several reviews summarizing the research efforts on FPR1 and FPR2 agonists, including natural ligands, have been published [4], [11], [12], [13], [14], [15], [16]. However, less attention has focused on natural FPR1 antagonists. Natural products traditionally have played an important role in drug discovery and were the basis of most early medicines [17]. The potential of natural products as sources for new drugs is still largely unexplored, and only a small fraction of the products present in existing plants, fungi, microorganisms, and animals have been investigated so far. Previously, we reported that many FPR1 antagonists contain OH groups, which can serve as H-bond donors and/or acceptors upon binding to the receptor, and that this feature is much more characteristic of FPR1 antagonists than agonists [16]. Because natural compounds in general incorporate more oxygen atoms than synthetic compounds and drugs [18], this feature makes them attractive for screening as FPR1 antagonists. Furthermore, natural products contain more fused rings, but fewer rotatable bonds than synthetic medicinal compounds [18], and this particular feature is also characteristic of FPR1 antagonists [16], [19].