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Antiviral Research (v.94, #1)

Prelim II: Editorial Board (pp. ii).

Inside Back Cover: Notes to Authors (pp. ibc).

A humanized IgG but not IgM antibody is effective in prophylaxis and therapy of yellow fever infection in an AG129/17D-204 peripheral challenge mouse model by Brett A. Thibodeaux; Nina C. Garbino; Nathan M. Liss; Joseph Piper; Jacob J. Schlesinger; Carol D. Blair; John T. Roehrig (pp. 1-8).

► There are no specific treatments for human yellow fever (YF) infection. ► We have created human/murine chimeric IgG (cIgG) and cIgM antibodies for YF virus. ► The cIgG prophylactically protects AG129 mice from peripheral 17D-204 challenge. ► The cIgG is therapeutically active at 1day post-infection with 17D-204. ► The cIgM has no antiviral activity in vivo.Yellow fever virus (YFV), a member of the genus Flavivirus, is a mosquito-borne virus found in tropical regions of Africa and South America that causes severe hepatic disease and death in humans. Despite the availability of effective vaccines, YFV is responsible for an estimated 200,000 cases and 30,000 deaths annually. There are currently no prophylactic or therapeutic strategies approved for use in human YFV infections. Furthermore, implementation of YFV 17D-204 vaccination campaigns has become problematic due to an increase in reported post-vaccinal adverse events. We have created human/murine chimeric MAbs of a YFV-reactive murine monoclonal antibody (mMAb), 2C9, that was previously shown to protect mice from lethal YFV infection and to have therapeutic activity. The new chimeric (cMAbs) were constructed by fusion of the m2C9 IgG gene variable regions with the constant regions of human IgG and IgM and expressed in Sp2 murine myelomas. The 2C9 cMAbs (2C9-cIgG and 2C9-cIgM) reacted with 17D-204 vaccine strain in an enzyme-linked immunosorbent assay and neutralized virus in vitro similarly to the parent m2C9. Both m2C9 and 2C9-cIgG when administered prophylactically 24h prior to infection protected AG129 mice from peripheral 17D-204 challenge at antibody concentrations ⩾1.27μg/mouse; however, the 2C9-cIgM did not protect even at a dose of 127μg/mouse. The 17D-204 infection of AG129 mice is otherwise uniformly lethal. While the m2C9 was shown previously to be therapeutically effective in YFV-infected BALB/c mice at day 4 post-infection, the m2C9 and 2C9-cIgG demonstrated therapeutic activity only when administered 1day post-infection in 17D-204-infected AG129 mice.

Keywords: Yellow fever; Human monoclonal antibodies; Treatment; Prophylaxis

Inhibition of Hepatitis B virus replication by Phospholipid scramblase 1 in vitro and in vivo by Jing Yang; Xiangqian Zhu; Juan Liu; Xiaoran Ding; Mingming Han; Wei Hu; Xuejun Wang; Zhe Zhou; Shengqi Wang (pp. 9-17).

► PLSCR1 proteins had the antiviral activity against HBV in cell cultures. ► PLSCR1 proteins had the antiviral activity against HBV in a mouse model. ► PLSCR1 suppressed HBV replication through inhibition of HBV RNAs. ► The expression of PLSCR1 was involved in HBV replication.Human Phospholipid scramblase 1 (PLSCR1) is an α/β interferon-inducible protein that mediates antiviral activity against RNA viruses including vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). In the present study, we investigated the antiviral activity of PLSCR1 protein against HBV (Hepatitis B virus). Firstly, PLSCR1 mRNA and protein expression was found to be downregulated in HepG2 cells after HBV infection. Then by performing co-transient-transfection experiments in cells and hydrodynamics-based transfection experiments in mice using a HBV expression plasmid and a PLSCR1 expression plasmid, we found that PLSCR1 inhibited HBV replication in vitro and in vivo through a significant reduction in the synthesis of viral proteins, DNA replicative intermediates and HBV RNAs. We also demonstrated that the antiviral action of PLSCR1 against HBV occurs, partly at least, by activating the Jak/Stat pathway. In conclusion, our results suggest that the expression of PLSCR1 is involved in HBV replication and that PLSCR1 has antiviral activity against HBV.

Keywords: Hepatitis B virus (HBV); Phospholipid scramblase 1 (PLSCR1); Antiviral activity; Interferon (IFN)

Characterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease by Manolya Ezgimen; Huiguo Lai; Niklaus H. Mueller; Kyungae Lee; Gregory Cuny; David A. Ostrov; Radhakrishnan Padmanabhan (pp. 18-24).

► Some potent inhibitors of WNV NS2B/NS3pro by compounds belonging to the 8-HQ class. ► The N1 of 8-HQ ring is important for inhibition of protease activity. ► The mode of inhibition of this class of compounds is by competing with the substrate binding to the active site.West Nile virus (WNV) is a mosquito-borne member of flaviviruses that causes significant morbidity and mortality especially among children. There is currently no approved vaccine or antiviral therapeutic for human use. In a previous study, we described compounds containing the 8-hydroxyquinoline (8-HQ) scaffold as inhibitors of WNV serine protease (NS2B/NS3pro) in a high throughput screen (HTS) using the purified WNV NS2B/NS3pro as the target. In this study, we analyzed potencies of some commercially available as well as chemically synthesized derivatives of 8-HQ by biochemical assays. An insight into the contribution of various substitutions of 8-HQ moiety for inhibition of the protease activity was revealed. Most importantly, the substitution of the N1 of the 8-HQ ring by –CH– in compound 26 significantly reduced the inhibition of the viral protease by this naphthalen-1-ol derivative. The kinetic constant (K _i) for the most potent 8-HQ inhibitor (compound 14) with an IC₅₀ value of 2.01±0.08μM using the tetra-peptide substrate was determined to be 5.8μM. This compound inhibits the WNV NS2B/NS3pro by a competitive mode of inhibition which is supported by molecular modeling.

Keywords: West Nile virus protease inhibitors; Molecular modeling and docking; Competitive inhibitors of West Nile virus protease; Structure activity relationship study among 8-hydroxyquinoline derivatives

A DNA vaccination regime including protein boost and electroporation protects cattle against foot-and-mouth disease by V. Fowler; L. Robinson; B. Bankowski; S. Cox; S. Parida; C. Lawlor; D. Gibson; F. O’Brien; B. Ellefsen; D. Hannaman; H.-H. Takamatsu; P.V. Barnett (pp. 25-34).

► Cattle are protected against FMDV following a DNA vaccination regime involving protein boost. ► Vaccinated cattle developed a good humoral and cell mediated responses. ► The immune response was enhanced using GM-CSF and in vivo electroporation.Protection against foot-and-mouth disease (FMD) using DNA technology has been documented for sheep and pigs but not for the highly susceptible species of cattle.Twenty-five Holstein Friesian cross-bred cattle were vaccinated twice, 21days apart, with a DNA vaccine containing the capsid coding region (P1) along with the non-structural proteins 2A, 3C and 3D (pcDNA3.1/P1-2A3C3D) of O₁ Kaufbeuren alone or coated onto PLG (d,l-lactide-co-glycolide) microparticles. In some pcDNA3.1/P1-2A3C3D was also combined with an adjuvant plasmid expressing bovine granulocyte macrophage colony stimulating factor (GM-CSF). DNA vaccinations were administered intramuscularly with, or without, the use of electroporation and at 42days post primary vaccination cattle received a protein boost of 146S FMD virus (FMDV) antigen and non-structural protein 3D. For comparison, four cattle were vaccinated with a conventional FMD vaccine and two more included as unvaccinated controls. Apart from those immunised with PLG microparticles all cattle were challenged with 10⁵ TCID₅₀ cattle adapted O₁ Lausanne FMDV virus at day 93 post primary vaccination.All DNA vaccinated cattle regardless of regime developed good humoral and cell mediated responses prior to challenge. The best overall virus neutralising antibody, IFN-γ and clinical protection (75%) were seen in the cattle whereby the DNA was delivered by electroporation. In contrast, only 25% of cattle vaccinated with the DNA vaccine without electroporation were clinically protected. The addition of GM-CSF in combination with electroporation further improved the efficacy of the vaccine, as demonstrated from the reduction of clinical disease and virus excretions in nasal swabs.We thus demonstrate for the first time that cattle can be clinically protected against FMDV challenge following a DNA prime-protein boost strategy, and particularly when DNA vaccine is combined with GM-CSF and delivered by electroporation.

Keywords: Foot-and-mouth disease; DNA vaccination; Cattle; Protection

Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus by Silvia Meneghesso; Evelien Vanderlinden; Annelies Stevaert; Christopher McGuigan; Jan Balzarini; Lieve Naesens (pp. 35-43).

► Uridine 5′-triphosphate derivatives can inhibit influenza RNA polymerase. ► Application of ProTide approach to uridine-based nucleoside analogues is reported. ► Two ProTides derived from 2′-fluoro-2′-deoxyuridine show moderate antiviral activity whilst parent nucleoside is inactive. ► Slow processing of ProTide is causing relatively low antiviral activity.Uridine-based nucleoside analogues have often been found to have relatively poor antiviral activity. Enzymatic assays, evaluating inhibition of influenza virus RNA polymerase, revealed that some uridine triphosphate derivatives displayed inhibitory activity on UTP incorporation into viral RNA. Here we report the synthesis, antiviral activity and enzymatic evaluation of novel ProTides designed to deliver the activated (monophosphorylated) uridine analogues inside the influenza virus-infected cells. After evaluation of the activation profile we identified two ProTides with moderate antiviral activity in MDCK cells (23a, EC₉₉=49±38μM and23b, EC₉₉⩾81μM) while the corresponding nucleoside analogue (2′-fluoro-2′-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation.

Keywords: Uridine-based nucleoside analogues; ProTide; RNA polymerase; Carboxypeptidase Y

Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox – An animal model of smallpox by Scott Parker; Nanhai G. Chen; Scott Foster; Hollyce Hartzler; Ed Hembrador; Dennis Hruby; Robert Jordan; Randall Lanier; George Painter; Wesley Painter; John E. Sagartz; Jill Schriewer; R. Mark Buller (pp. 44-53).

► CMX001 and ST-246 have efficacy in the C57BL/6 mousepox models of smallpox and monkeypox. ► Protection is provided to C57Bl/6 mice when CMX001 or ST-246 is initiated on or before day 6. ► Appearance of rash occurs outside of the window of efficacious therapeutic intervention. ► Viral DNA can be detected from day 4 in blood and from day 2 in oropharyngeal secretions. ► Viral DNA in oropharyngeal secretions is the optimal biomarker to trigger intervention.The human population is currently faced with the potential use of natural or recombinant variola and monkeypox viruses as biological weapons. Furthermore, the emergence of human monkeypox in Africa and its expanding environs poses a significant natural threat. Such occurrences would require therapeutic and prophylactic intervention with antivirals to minimize morbidity and mortality of exposed populations. Two orally-bioavailable antivirals are currently in clinical trials; namely CMX001, an ether-lipid analog of cidofovir with activity at the DNA replication stage and ST-246, a novel viral egress inhibitor. Both of these drugs have previously been evaluated in the ectromelia/mousepox system; however, the trigger for intervention was not linked to a disease biomarker or a specific marker of virus replication. In this study we used lethal, intranasal, ectromelia virus infections of C57BL/6 and hairless SKH1 mice to model human disease and evaluate exanthematous rash (rash) as an indicator to initiate antiviral treatment. We show that significant protection can be provided to C57BL/6 mice by CMX001 or ST-246 when therapy is initiated on day 6 post infection or earlier. We also show that significant protection can be provided to SKH1 mice treated with CMX001 at day 3 post infection or earlier, but this is four or more days before detection of rash (ST-246 not tested). Although in this model rash could not be used as a treatment trigger, viral DNA was detected in blood by day 4 post infection and in the oropharyngeal secretions (saliva) by day 2–3 post infection – thus providing robust and specific markers of virus replication for therapy initiation. These findings are discussed in the context of current respiratory challenge animal models in use for the evaluation of poxvirus antivirals.

Keywords: Ectromelia; Bioterrorism; Rash; Variola; Monkeypox; Biological weapon

Predicting sustained viral response to hepatitis C using a rapid and simple IL28B rs8099917 genotyping assay by Wei Li; Yanli Zeng; Junjie Wang; Bin Zhou; Jian Zhang; Hao Zhang; Jingtao Li; Yingsong Wu; Rifat Hamoudi; Yuanping Zhou (pp. 54-56).

► A new IL28B rs8099917 genotyping assay with 98.2% specificity. ► The new assay can be implemented using standard PCR equipments. ► IL28B genotyping could provide treatment-response information for clinician.Recent studies showed that two single nucleotide polymorphisms (SNPs) (rs12979860 and rs8099917) near the gene IL28B coding for IFNλ3 were associated with the antiviral treatment response of the combination therapy of pegIFN plus RBV. We established the use of tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR) for detecting IL28B rs8099917 genotype (T>G) in 56 Chinese chronic hepatitis C patients infected with Hepatitis C Virus (HCV) genotype 1. The new assay showed 98.2% specificity, and was confirmed by direct sequencing. Among the 56 samples, TT genotype and TG genotype accounted for 80.4% (45/56) and 19.6% (11/56), respectively. GG genotype was not found. The proportion of responders in TT group was higher than that in TG group (68.9% vs. 27.3%, p=0.029). For HCV clinical decision-making, using the new assay, rs8099917 genotyping could provide similar information to rs12979860 genotyping due to a strong association between the two SNPs in Chinese patients. The assay system in this study can be implemented using basic laboratory equipments, making it convenient for clinical and research purposes.

Keywords: Abbreviations; HCV; Hepatitis C Virus; RBV; ribavirin; SOC; standard of care; CHC; chronic hepatitis C; SVR; sustained virological response; GWAS; genome-wide association study; SNP; single nucleotide polymorphism; PCR; polymerase chain reaction; ARMS; tetra-primer amplification refractory mutation system; EVR; early virological responseHepatitis C Virus; IL28B; Treatment response; Single nucleotide polymorphism

The 1α,25-dihydroxy-vitamin D3 reduces dengue virus infection in human myelomonocyte (U937) and hepatic (Huh-7) cell lines and cytokine production in the infected monocytes by Henry Puerta-Guardo; Sergio Isaac De la Cruz Hernández; Victor H. Rosales; Juan E. Ludert; Rosa María del Angel (pp. 57-61).

► Vitamin D treatment inhibits dengue virus infection in hepatic and monocytic cells. ► The effect of vitamin D on viral replication is cell type dependent. ► Vitamin D treatment modulates the cytokine response of infected monocytes.Dengue is the most important mosquito-borne viral infection in humans. Recent evidence suggests that vitamin D influences virus replication. In this work, the effect of vitamin D treatment on dengue virus infection in human hepatic Huh-7 cells and on virus infection and cytokine production in the human monocytic U937 cells was evaluated. Exposure to 1α,25-dihydroxy-vitamin D3, resulted in a significant reduction in the number of infected cells, in conditions where cell viability was not affected. Viral replication in monocytic cells was more susceptible to vitamin D3 than replication in the hepatic cells. Moreover, vitamin D3 significantly reduced the levels of proinflammatory cytokines (TNF-α, IL-6, IL-12p70 and IL-1β) produced by infected U937 cells. These results suggest that vitamin D3 may represent a potentially useful antiviral compound.

Keywords: Dengue; Dengue virus; Vitamin D; Cytokines; Antivirals

Foot-and-mouth disease virus causes a decrease in spleen dendritic cells and the early release of IFN-α in the plasma of mice. Differences between infectious and inactivated virus by C. Langellotti; V. Quattrocchi; C. Alvarez; M. Ostrowski; V. Gnazzo; P. Zamorano; M. Vermeulen (pp. 62-71).

► We study the changes in splenic dendritic cells by infectious and inactivated foot-and-mouth disease virus. ► After infection T response is restored after 5days associated to IL-10 and IFN-γ production. ► Inactivated virus increases the percentage of splenic plasmacytoid dendritic cells and IL-10 release. ► Inactivated virus induces a T regulatory profile associated to inhibition of T response.Foot-and-mouth disease (FMD) is a highly contagious and acute viral disease of cloven-hoofed animals. From an economical point of view, it is the most important disease of livestock worldwide. It is known that the virus interacts with dendritic cells, both in the natural host and in mice, but the impact of this interaction on the adaptive immune response is controversial. Currently available vaccines are based on inactivated forms of the FMD virus. Little is known about the differences between infectious and inactivated virus, in terms of dendritic cell subsets involved in immune response activation. The present work, which was carried out in the murine model, shows that live virus infection induces a reduction in splenic dendritic cell subsets. In addition, lymphocyte proliferation is inhibited in the early stages of infection associated with IFN-α induction, but is restored to normal values 5days post-infection when pro-inflammatory cytokines was produced. In contrast, the inactivated virus increases the percentage of plasmacytoid dendritic cells in the spleen and the production of IL-10, which triggers the activation of a T regulatory response.

Keywords: Abbreviations; FMDV; foot-and-mouth disease virus; iFMDV; inactivated FMDV; pDC; plasmacytoid dendritic cells; Treg; T regulatory lymphocytes; IFN-α; interferon-alpha; MFI; mean fluorescence intensityFoot-and-mouth disease virus; Dendritic cells; Inactivated viral particles; CD4; ⁺; CD25; ⁺; Foxp3; ⁺; T lymphocytes activation; Interferon type 1

Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease by Christoph Nitsche; Mira A.M. Behnam; Christian Steuer; Christian D. Klein (pp. 72-79).

► Di- and tripeptides with a cinnamyl cap are described as inhibitors of the DEN protease. ► These compounds possess a strong inhibitory potency. ► Selectivity is significant, shown in a counterscreen against thrombin. ► Compounds are free from strongly reactive, non-drug-like electrophiles. ► Clear structure–activity relationships allow design of optimized derivatives.New chemotherapeutics against Dengue virus and related flaviviruses are of growing interest in antiviral drug discovery. The viral serine protease NS2B-NS3 is a promising target for the development of such agents. Drug-like inhibitors of this protease with high affinity to the target are not available at the moment. The present work describes the discovery of new retro di- and tripeptide hybrids that do not necessarily require an electrophilic “warhead” to achieve affinities in the low micromolar range. The most active sequence in this series is the tripeptide R-Arg-Lys-Nle-NH₂. By variation of the N-terminal groups (R) it could be shown that the previously described arylcyanoacrylamide moiety is a preferable group in this position. Retro tripeptide hybrids were found to be more active and more selective than retro dipeptide hybrids. A significant selectivity towards the Dengue virus protease could be shown in a counterscreen with thrombin and the West Nile virus protease. Alternative sequences to R-Arg-Lys-Nle-NH₂ did not have higher affinities towards the Dengue virus protease, similar to retro-inverse sequences withd-lysine andd-arginine residues. The results of a competition assay with the known inhibitor aprotinin indicate that the N-terminal arylcyanoacrylamide residue of this compound class binds near the catalytic center of the enzyme.

Keywords: Hybrid retro peptides; Dengue virus; West Nile virus; Thrombin; NS2B-NS3 protease

Advanced morpholino oligomers: A novel approach to antiviral therapy by Travis K. Warren; Amy C. Shurtleff; Sina Bavari (pp. 80-88).

► PMOs can be rapidly designed and produced in response to emergency medical needs. ► PMOs exhibit antiviral activity against a variety of viruses in in vivo models. ► Novel design strategies may improve the broad-spectrum antiviral activity of PMOs.Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense oligonucleotide analogs that are designed to interfere with translational processes by forming base-pair duplexes with specific RNA sequences. Positively charged PMOs (PMO plus™) are effective for the postexposure protection of two fulminant viral diseases, Ebola and Marburg hemorrhagic fever in nonhuman primates, and this class of antisense agent may also have possibilities for treatment of other viral diseases. PMOs are highly stable, are effective by a variety of routes of administration, can be readily formulated in common isotonic delivery vehicles, and can be rapidly designed and synthesized. These are properties which may make PMOs good candidates for use during responses to emerging or reemerging viruses that may be insensitive to available therapies or for use during outbreaks, especially in regions that lack a modern medical infrastructure. While the efficacy of sequence-specific therapies can be limited by target-site sequence variations that occur between variants or by the emergence of resistant mutants during infections, various PMO design strategies can minimize these impacts. These strategies include the use of promiscuous bases such as inosine to compensate for predicted base-pair mismatches, the use of sequences that target conserved sites between viral strains, and the use of sequences that target host products that viruses utilize for infection.

Keywords: Antisense; Morpholino; Phosphorodiamidate; Biodefense; Ebola virus; Marburg virus

Novel anti-HIV-1 activity produced by conjugating unsulfated dextran with polyl-lysine by Kosuke Nakamura; Takahiro Ohtsuki; Haruyo Mori; Hiroo Hoshino; Ariful Hoque; Atsushi Oue; Fumie Kano; Hiromi Sakagami; Ken-ichi Tanamoto; Hiroshi Ushijima; Nana Kawasaki; Hiroshi Akiyama; Haruko Ogawa (pp. 89-97).

► Conjugation of dextran chains to a polyl-lysine produced a high anti-HIV-1 activity. ► The PLL–Dex suppressed both the macrophage-tropic R5 and T-cell line tropic X4 virus. ► The cytotoxicity of PLL was remarkably decreased by conjugation with Dex. ► PLL–Dex was effective against a clinically isolated R5 virus in primary PBMC. ► Acting both on cells and virus, PLL–Dex inhibits cell binding and entry of the virus.A conjugate of polyl-lysine (PLL) with unsulfated dextran produced by reductive amination was found to have remarkable anti-HIV-1 activity against both the macrophage-tropic R5 virus Ba-L and T-cell line tropic X4 virus IIIB strains, although neither PLL nor dextran has such activity. The conjugate is a pseudoproteoglycan (pseudoPG) that simulates the structure of a proteoglycan. Conjugation with dextran was found to produce an antiviral effect in three kinds of assay systems including a human CD4⁺ T-cell line, and the pseudoPG synthesized using 10kDa PLL and 10kDa dextran showed EC₅₀ 4–40 times lower than that of sulfated dextran or heparin against Ba-L and EC₅₀ equal to that against IIIB, indicating that PLL–dextran (PLL–Dex) was more effective against R5 virus than sulfated polysaccharides. PLL–Dex significantly suppressed a clinically isolated R5 virus from primary peripheral blood mononuclear cells. PLL–Dex interacted with the virus during adsorption to the cell and also decreased virus entry into the cell, suggesting PLL–Dex has multiple preventive mechanisms against HIV-1.

Keywords: Unsulfated glycan; Dextran; α-Poly; l; -lysine; HIV-1 suppression; Pseudoproteoglycan; Conjugation

Induction of type I interferon by high-molecular poly-γ-glutamate protects B6.A2G- Mx1 mice against influenza A virus by Ho-Jin Moon; Jong-Soo Lee; Young-Ki Choi; Jie-Yeun Park; Melbourne R. Talactac; Mohammed Y.E. Chowdhury; Haryoung Poo; Moon-Hee Sung; Ji-Hoon Lee; Jae U. Jung; Chul-Joong Kim (pp. 98-102).

► Replication of influenza A virus is inhibited by Myxovirus resistant (Mx) proteins. ► Type I interferons (IFNs) stimulate expression of Mx proteins. ► γ-PGA, a safe natural substance, induces secretion of IFNs. ► IFNs induced by γ-PGA stimulate expression of Mx proteins. ► Thereby, pretreated γ-PGA protects Mx1 congenic mice against influenza A virus.In addition to development of vaccines and synthetic antiviral drugs, recent studies have advocated the use of natural substances that inhibit or prevent viral infections. High-molecular-weight poly-γ-glutamate (HM-γ-PGA) produced by Bacillus subtilis chungkookjang was evaluated for anti-influenza virus activity. HM-γ-PGA induced type I interferons (IFNs), which in turn stimulated expression of Myxovirus resistant 1 protein and IFN-related proteins in vitro. In the B6.A2G- Mx1 mouse model, which mimics the innate immune system of humans, treatment with HM-γ-PGA enhanced the antiviral state of mice and protected them against highly pathogenic influenza A virus. Naturally synthesized HM-γ-PGA has potent anti-influenza activity and may be a useful means for control of influenza virus.

Keywords: High-molecular-weight poly-γ-glutamate; Myxovirus resistance protein; Interferon type I; B6.A2G-; Mx1; mouse; Influenza A virus

Combinations of favipiravir and peramivir for the treatment of pandemic influenza A/California/04/2009 (H1N1) virus infections in mice by E. Bart Tarbet; Masako Maekawa; Yousuke Furuta; Y.S. Babu; John D. Morrey; Donald F. Smee (pp. 103-110).

► Favipiravir and peramivir were evaluated against influenza A virus in mice. ► Combinations of favipiravir and peramivir increased survivors by 10–50%. ► Three-dimensional analyses of drug interactions indicate strong synergy.Favipiravir, an influenza virus RNA polymerase inhibitor, and peramivir, an influenza virus neuraminidase inhibitor, were evaluated alone and in combination against pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Infected mice were treated twice daily for 5d starting 4h after virus challenge. Favipiravir was 40%, 70%, and 100% protective at 20, 40, and 100mg/kg/d. Peramivir was 30% protective at 0.5mg/kg/d, but ineffective at lower doses when used as monotherapy. Combinations of favipiravir and peramivir increased the numbers of survivors by 10–50% when the 0.025, 0.05, and 0.1mg/kg/d doses of peramivir were combined with 20mg/kg/d favipiravir and when all doses of peramivir were combined with 40mg/kg/d favipiravir. Three-dimensional analysis of drug interactions using the MacSynergy method indicates strong synergy for these drug combinations. In addition, an increase in lifespan for groups of mice treated with drug combinations, compared to the most effective monotherapy group, was observed for the 0.025, 0.05, and 0.1mg/kg/d doses of peramivir combined with favipiravir at the 20mg dose level. Therefore, the 20mg/kg/d dose of favipiravir was selected for further combination studies. Increased survival was exhibited when this dose was combined with peramivir doses of 0.1, 0.25 and 0.5mg/kg/d (1mg/kg/d of peramivir alone was 100% protective in this experiment). Improved body weight relative to either compound alone was evident using 0.25, 0.5, and 1mg/kg/d of peramivir. Significant reductions in lung hemorrhage score and lung weight were evident on day 6 post-infection. In addition, virus titers were reduced significantly on day 4 post-infection by combination therapy containing favipiravir combined with peramivir at 0.25 and 0.5mg/kg/d. These data demonstrate that combinations of favipiravir and peramivir perform better than suboptimal doses of each compound alone for the treatment of influenza virus infections in mice.

Keywords: Drug combination; Favipiravir; T-705; Peramivir; Antiviral

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Antiviral Research (v.94, #1)