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DISCUSSION

Many members of the family Flaviviridae are important human and veterinary pathogens. Especially, several members of the Flavivirus genus are considered (re)emerging viruses, which are defined as pathogens that have existed previously or have newly appeared in a population and are increasing in incidence or geographic range (17) . Successful treatment of HCV infections has been achieved in the last couple of years with the development of highly effective direct-acting antiviral (DAA) therapies (18) . Moreover, favipiravir, also known as T-705 or Avigan, is in use against YFV and WNV infections (as well as infections caused by arenaviruses, bunyaviruses, and alphaviruses) (19) , and host-directed compounds, such as cyclophilin inhibitors (20, 21) and ␣-glucosidase inhibitors (22) , have been evaluated in clinical trials to control HCV and dengue virus (DENV) infections, respectively. Furthermore, prophylactic options, such as vaccination, have been developed for YFV, JEV, and tick-borne encephalitis virus (TBEV) (23), as well as for DENV, although the vaccine against DENV suffers from limited efficacy (24, 25) . On the other hand, vaccines for humans to combat HCV, WNV, and ZIKV are not available (26) . Taken together, the available panel of prophylactic and antiviral treatment options against flavivirus infections in human and animals remains limited, thus emphasizing the need for the development of effective and reliable drugs/vaccines. Following a screening which aimed at identifying anti-HCoV-229E compounds, we have described a potent small-compound inhibitor, K22, which efficiently inhibited coronavirus replication and was recently shown to additionally inhibit a wide range of virus species within the families Coronaviridae and Arteriviridae (12, 13) . K22 has been shown to act on early postentry stages of coronavirus replication and to target membrane-bound RNA synthesis by interfering with the establishment of virus-induced replicative structures. Importantly, HCoV-229E mutants that were able to replicate in the presence of K22 were isolated following several virus passages on K22-treated cells. These escape mutants contained amino acid substitutions in nonstructural protein 6 (nsp6; H121L, M159V) that were associated with K22 resistance. Coronavirus nsp6
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Inhibiting Viral Replication

Viral proteins are the working molecules for viral biosynthesis, among which RdRp plays an important role in hantaviral transcription and replication and is considered a desirable drug target. The pyrazine derivative Favipiravir and the nucleoside analogs Ribavirin (RBV) and ETAR have been tested effective antihantaviral drugs that directly or indirectly affect the biological function of RdRp. Favipiravir (Avigan; T-705) was initially discovered in 2002 as an antiviral drug selectively inhibiting the RdRp of influenza virus and then reported to have a high activity against a panel of Bunyaviruses (Gowen et al., 2007; Westover et al., 2016) . Favipiravir could attenuate the viral RNA replication level and decrease the progeny virus yield of SNV and ANDV in vitro. In vivo studies, including non-lethal SNV challenged and lethal ANDV challenged hamster model, demonstrated that oral administration favipiravir at the dosage of 100 mg/kg twice daily could prominently reduce viral load in hamster serum and various organs and resulted in 100% survival in the ANDV lethal infection model (Safronetz et al., 2013) . Delayed favipiravir administration after the onset of viremia exerted no protective effects against ANDV infection. Notably, there is no reported clinical trial with favipiravir as an antiviral treatment in HFRS and HCPS.
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Introduction

The major clinical features of SFTS include high fever (body temperature �38˚C), fatigue, malaise, anorexia, nausea, vomiting, diarrhea, thrombocytopenia, leukocytopenia, and abdominal pain [16, 17] . In severe cases, SFTS can include central nervous system manifestations, hemorrhagic signs, and multiple organ dysfunction, which can lead to death [18] [19] [20] [21] . No vaccines or therapeutics specific for SFTS have been approved for human use. Recently, a Phase 3 clinical trial of favipiravir (Avigan), a drug approved for the treatment of influenza virus infection in Japan, was initiated to expand its indication to SFTS treatment [22] . Monoclonal antibodies or convalescent sera from SFTS patients were tested to identify potential therapeutic intervention targets, resulting in the identification of SFTSV glycoproteins as molecules required for host cell entry [23, 24] and also as critical targets for virus neutralization through the development of humoral immunity. Both the Gn and Gc envelope glycoproteins of SFTSV are type I transmembrane proteins, and Gc is proposed to be a membrane fusion protein critical for SFTSV infection [25] . This has also been shown in Rift Valley fever virus (RVFV) [26] , which is a well-known phlebovirus, whereas the function of Gn remains largely elusive across all other species in the genus Phlebovirus. The structure of the Gn head domain, which is composed of three subdomains, was resolved in SFTSV and RVFV [27] . However, the homology and arrangement within subdomains differ considerably between the two viruses, and the structure of the Gn stem domain still remains unknown. Moreover, the generation of an antibody for these targets in infected humans is rare, due to the presence of immunodominant decoy epitopes in the nucleoprotein [28] , which is a common phenomenon in a pathogenic virus-infected host [29] . In animal models, however, the protective effect of human convalescent sera was shown, suggesting that antibody therapy is possible [30] . Thus far, MAb4-5 is the only human neutralizing monoclonal antibody reported, and it was developed using a combinatorial human antibody library from five patients [31] . MAb4-5 binds to domain III of SFTSV Gn glycoprotein [27] . The neutralizing effect of MAb4-5 has been shown only in in vitro, and its in vivo efficacy remains to be shown.