The present study showed that the

The present study showed that the FPR2 antagonists PBP10 and BOC2 are potent antiviral molecules in vitro against a broad range of IAV and B viruses. Consistently, our previous report showed that FPR2 plays a deleterious role during IAV infections and that another FPR2 antagonist WRW4 inhibits IAV replication in vitro and in vivo. Mechanistically, the effect of PBP10 and BOC2 was abolished by treating the cells with U0126, a specific ERK pathway inhibitor. The antiviral role of these molecules occurs through ERK activation, a pathway necessary for the viral life cycle in vitro and in vivo (Droebner et al., 2011, Marjuki et al., 2011, Pleschka et al., 2001). In vivo, administration of BOC2 to infected mice protected them from lethal IAV infections. These results confirm our previous preclinical studies showing that another inhibitor of FPR2, WRW4 efficiently protected mice against lethal IAV infections (Tcherniuk et al., 2016). Protein sequence alignment (Fig. 7) shows 76% amino Verapamil HCl identity between human and mouse FPR2 (85% when considering similar residues) and 97% amino acid identity between human and monkey FPR2 (98% when considering similar residues). This sequence similarity is likely to explain the conserved inhibitory effect of WRW4 and BOC2 in mice. It is noteworthy that WRW4 or BOC2 administration in a prophylactic manner also had a protective effect. Thus, FPR2 antagonism might be explored not only as a new treatment for influenza but also to prevent the disease. This effect would be particularly valuable in case of a pandemic. Indeed, although preventive vaccination exists, based on our knowledge of previous pandemic plans, the delay of 6–12 months to produce a pandemic vaccine cannot fit with a required rapid response (Webby and Webster, 2003). Vaccines are reduced to specific viral strains that should first be identified, produced in large amount and their inactivation controlled. In addition, they are accessible only to a small, privileged fraction of the world population. Finally, the increasing skepticism towards vaccination has led to a drop in immunization coverage rates. The development of new antiviral drugs thus appears as a relevant strategy. Regarding the advantage of FPR2 antagonists acting in a therapeutic or prophylactic manner, it would not only prevent virus from spreading from human to human but also protect the population before infection occurs. In contrast to the current antiviral drugs, FPR2 antagonists could most likely be used without the emergence of resistant viruses. Indeed, the current commercialized antivirals target viral proteins which are highly subjected to mutations. In contrast, blocking a cellular receptor will slow down viral growth and at the same time diminish the probability of the virus escaping from mutation pressure since the virus is unable to modify the host genome. It is also noteworthy that mice lacking FPR2 develop normally, and their lifespan in a pathogen-free facility is equivalent to wild-type mice (Chen et al., 2010). This suggests that FPR2 is not a crucial receptor for cellular functions which reinforces the interest of testing FPR2 inhibitors as novel therapeutic against influenza. It is also noteworthy that FPR2 belongs to the family of G-protein coupled receptors (GPCRs). GPCRs have been one of the most popular targets for drug developers. According to a recent publication, 30–50% of commercialized drugs exert their effect through GPCRs and from 2005-2014, 25% of novel approved drug from US Food and Drug Administration target GPCRs (Fang et al., 2015). FPR2 plays a key role in inflammatory processes and thus is also a major target for drug developers. However, to our knowledge FPR2 inhibitors did not go through clinical trials yet. The reasons might be multiple. First, in comparison to other receptors, the precise role of FPR2 (pro-inflammatory versus resolution of inflammation) is only emerging. Then, FPR2 also belongs to the FPR family, in which two other FPRs were described in humans (FPR1 and 3) and all FPRs have similarities in their amino acid sequences. While WRW4 and PBP10 are highly specific inhibitors of FPR2, BOC2 is less specific and also inhibits FPR1. Thus, a limitation in the use of FPR2 antagonists is to develop very specific small molecules against FPR2. Unfortunately, the discovery of specific molecules targeting GPCRs is very intractable and currently, bio-therapeutic has been demonstrated to be a better approach (Mujic-Delic et al., 2014). Antibodies to GPCRs have been difficult to develop since they are very unstable when purified. However, with the recent technical progress made, antibodies/nanobodies directed against FPR2 will most likely be very important tools in the future for drug discovery.