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Antiviral Research (v.79, #3)
A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations by Eloan dos Santos Pinheiro; Octavio Augusto Ceva Antunes; Joseph M.D. Fortunak (pp. 143-165).
It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely irrelevant, except for “advanced salvage” drugs such as enfuvirtide. In resource-poor settings cost is a huge factor that limits drug access, resulting in high rates of new infection and subsequent mortality. IP coverage, where granted, can keep access prices for essential ARVs higher than would otherwise be the case. Large, innovator companies have made drugs available at prices very close to the cost of manufacturing for “lowest income” countries. Generic providers in India and elsewhere provide the largest supply of drugs for the developing world. The recent issuance of Voluntary and Compulsory Licenses (VLs, CLs) through the World Trade Organization's TRIP (Treaty Respecting Intellectual Property) provisions arguably contribute to bringing down access prices. The utilization of improved science, pooled purchasing and intelligent procurement practices all definitely contribute to access. This work surveys the production processes for several critical ARVs. These are discussed in terms of scale up, raw material/intermediates and active pharmaceutical ingredient (API) costs. In some cases new routes to APIs or critical intermediates are needed. Based on potential new chemistries, there are significant opportunities to reduce cost for a number of critical ARVs.
Keywords: HIV-1; Drugs; Second line; Synthesis; Prices; Efavirenz; Tenofovir Disoproxil Fumarate; TDF; Emtricitabine; FTC; Ritonavir; Lopinavir; Kaletra; Atazanavir
Progress in identifying virulence determinants of the 1918 H1N1 and the Southeast Asian H5N1 influenza A viruses by Christopher F. Basler; Patricia V. Aguilar (pp. 166-178).
The 1918 pandemic H1N1 influenza virus and the recently emerged Southeast Asian H5N1 avian influenza virus are unique among influenza A virus isolates in their high virulence for humans and their lethality for a variety of animal species without prior adaptation. Reverse genetic studies have implicated several viral genes as virulence determinants. For both the 1918 and H5N1 viruses, the hemagglutinin and the polymerase complex contribute to high virulence. Non-structural proteins NS1 and PB1-F2, which block host antiviral responses, also influence pathogenesis. Additionally, recent studies correlate high levels of viral replication and induction of strong proinflammatory responses with the high virulence of these viruses. Defining how individual viral proteins promote enhanced replication, inflammation and severe disease will provide insight into the pathogenesis of severe influenza virus infections and suggest novel therapeutic approaches.
Keywords: Influenza virus; Virulence; Pathogenesis; 1918; H5N1; Pandemic; Avian influenza; Antiviral therapy
A case for developing antiviral drugs against polio by Marc S. Collett; Johan Neyts; John F. Modlin (pp. 179-187).
Polio eradication is within sight. In bringing the world close to this ultimate goal, the Global Polio Eradication Initiative (GPEI) has relied exclusively on the live, attenuated oral poliovirus vaccine (OPV). However, as eradication nears, continued OPV use becomes less tenable due to the incidence of vaccine associated paralytic poliomyelitis (VAPP) in vaccine recipients and disease caused by circulating vaccine-derived polioviruses (cVDPVs) in contacts. Once wild poliovirus transmission has been interrupted globally, OPV use will stop. This will leave the inactivated poliovirus vaccine (IPV) as the only weapon to defend a polio-free world. Outbreaks caused by cVDPVs are expected post-OPV cessation, and accidental or deliberate releases of virus could also occur. There are serious doubts regarding the ability of IPV alone to control outbreaks. Here, we argue that antiviral drugs against poliovirus be added to the arsenal. Anti-poliovirus drugs could be used to treat the infected and protect the exposed, acting rapidly on their own to contain an outbreak and used as a complement to IPV. While there are no polio antiviral drugs today, the technological feasibility of developing such drugs and their probability of clinical success have been established by over three decades of drug development targeting the related rhinoviruses and non-polio enteroviruses (NPEVs). Because of this history, there are known compounds with anti-poliovirus activity in vitro that represent excellent starting points for polio drug development. Stakeholders must come to understand the potential public health benefits of polio drugs, the feasibility of their development, and the relatively modest costs involved. Given the timelines for eradication and those for drug development, the time for action is now.
Keywords: Polio eradication; Oral poliovirus vaccine (OPV); Inactivated poliovirus vaccine (IPV); Poliovirus; Vaccine-derived poliovirus (VDPV); Enteroviruses; Rhinoviruses; Antiviral drugs; Capsid inhibitors; Protease inhibitors; Replication inhibitors; Outbreak control; Drug development
Neutralization of hepatitis B virus (HBV) by human monoclonal antibody against HBV surface antigen (HBsAg) in chimpanzees by Se-Ho Kim; Yong Won Shin; Kwang-Won Hong; Ki-Hwan Chang; Kyung-Hwan Ryoo; Sang-Hoon Paik; Jin-Man Kim; Betsy Brotman; Wolfram Pfahler; Alfred M. Prince (pp. 188-191).
The virus neutralizing efficacy of HB-C7A, a human monoclonal antibody raised against the surface antigen of hepatitis B virus (HBsAg), was proved using hepatitis B virus (HBV)-naïve chimpanzees. One control chimpanzee which received 100CID50 of HBV, subtype adw, without HB-C7A antibody became infected by HBV as evidenced by the appearance of HBV DNA on week 10 and subsequent appearance of HBsAg, anti-HBc and anti-HBs in the serum. Two experimental chimpanzees were inoculated intravenously with same dose of HBV as the control chimpanzee, which was previously incubated with 0.1mg and 10mg of HB-C7A antibody prior to inoculation. HBV infection was not observed in the antibody-treated chimpanzees during 12 months of follow-up, exhibiting neither detectable HBsAg nor anti-HBc antibody. This work demonstrates the neutralization of HBV by HB-C7A monoclonal antibody and shows the possibility of prevention of HBV infection using this antibody in liver transplantation and exposure to HBV.
Keywords: Human monoclonal antibody; Hepatitis B virus (HBV); Hepatitis B virus surface antigen (HBsAg); Hepatitis B immune globulin (HBIG); Chimpanzee; Neutralization
Inhibition of HSV cell-to-cell spread by lactoferrin and lactoferricin by Håvard Jenssen; Kjersti Sandvik; Jeanette H. Andersen; Robert E.W. Hancock; Tore J. Gutteberg (pp. 192-198).
The milk protein lactoferrin (Lf) has multiple functions, including immune stimulation and antiviral activity towards herpes simplex virus 1 and 2 (HSV-1 and HSV-2); antiviral activity has also been reported for the N-terminal pepsin-derived fragment lactoferricin (Lfcin). The anti-HSV mode of action of Lf and Lfcin is assumed to involve, in part, their interaction with the cell surface glycosaminoglycan heparan sulfate, thereby blocking of viral entry. In this study we investigated the ability of human and bovine Lf and Lfcin to inhibit viral cell-to-cell spread as well as the involvement of cell surface glycosaminoglycans during viral cell-to-cell spread. Lf and Lfcin from both human and bovine origin, inhibited cell-to-cell spread of both HSV-1 and HSV-2. Inhibition of cell-to-cell spread by bovine Lfcin involved cell surface chondroitin sulfate. Based on transmission electron microscopy studies, human Lfcin, like bovine Lfcin, was randomly distributed intracellularly, thus differences in their antiviral activity could not be explained by differences in their distribution. In contrast, the cellular localization of iron-saturated (holo)-Lf appeared to differ from that of apo-Lf, indicating that holo- and apo-Lf may exhibit different antiviral mechanisms.
Keywords: Lactoferricin; Lactoferrin; Antiviral activity; Glycosaminoglycans; Herpes simplex virus
In vitro evaluation of neuraminidase inhibitors using the neuraminidase-dependent release assay of hemagglutinin-pseudotyped viruses by Ching-Yao Su; Shi-Yun Wang; Jiun-Jie Shie; King-Song Jeng; Nigel J. Temperton; Jim-Min Fang; Chi-Huey Wong; Yih-Shyun E. Cheng (pp. 199-205).
For the treatment of influenza virus infections, neuraminidase inhibitors (NAIs) that prevent the release of virus particles have been effective against most influenza strains. Several neuraminidase (NA) assays are available for the evaluation of NAIs. To understand the NAI functions under physiological conditions, assays mimicking viral particle release should be useful. We have constructed retrovirus-based reporter viruses that are pseudotyped with hemagglutinin (HA) glycoprotein by transfection of producer cells using plasmids expressing retroviral gag-pol, influenza HA, NA, and firefly luciferase genes. Similarly to the life cycle of influenza viruses, the release of pseudotype viruses also requires neuraminidase functions. This requirement was used to develop an assay to evaluate NAI activities by measuring inhibition of pseudotype virus production at different NAI concentrations. The pseudotype virus release assay was used to determine the IC50 values of Oseltamivir carboxylate, Zanamivir, and the novel phosphonate congeners of Oseltamivir against N1 group neuraminidases and their H274Y Oseltamivir carboxylate-resistant mutants. The deduced IC50 values obtained using the release assay correlated with those determined using the fluorogenic substrate 2′-(4-methylumbelliferyl)-α-d- N-acetylneuraminic acid (MUNANA) and also correlated with the infectivity results.
Keywords: Neuraminidase inhibitor; Pseudotype virus; Antiviral; Viral release assay; Drug resistance