Identification and Synthesis of Quinolizidines with Anti-Influenza A Virus Activity

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Avian influenza A (H5N1) infection: targets and strategies for chemotherapeutic intervention

In an avian flu pandemic, which drugs could be used to treat or prevent infection with influenza A (H5N1) virus? Foremost are the viral neuraminidase inhibitors oseltamivir and zanamivir, which have already been used to treat human influenza A (H1N1 and H3N2) and B virus infections. The use of the M2 ion channel blockers amantadine and rimantadine is compounded by the rapid development of drug resistance. Although formally approved for other indications (i.e. treatment of hepatitis C), ribavirin and pegylated interferon might also be useful for controlling avian flu. Combined use of the currently available drugs should be taken into account and attempts should be made to develop new strategies directed at unexplored targets such as the viral proteins hemagglutinin, the viral polymerase (and endonuclease) and the non-structural protein NS1. As has been shown for other viral infections, RNA interference could be a powerful means with which to suppress the replication of avian H5N1.     

抗流感病毒药物研究进展

流感病毒是人类健康的一大威胁。应对流感病毒的主要方式是疫苗和药物治疗。对可能大规模爆发的流感疫情来讲, 药物治疗是最好的控制流感病毒传播的手段。目前, 抗流感病毒药物包括已在俄罗斯上市的盐酸阿比朵尔和美国FDA批准的4个抗流感病毒药物, 后者根据作用机制的不同分为M2离子通道蛋白抑制剂和神经氨酸酶 (NA) 抑制剂。其中, NA抑制剂根据结构又可分为唾液酸类似物、苯甲酸衍生物、环己烯衍生物、环戊烷衍生物、吡咯烷衍生物及天然提取物6大类。本文简要介绍了上述各类已上市和临床在研药物的最新研究进展。     

Development of antivirals against influenza

Morbidity and mortality due to influenza virus infections remain a major problem throughout the world. Yearly, medical costs and loss of productivity resulting from influenza infection are estimated to be in the range of 12 dollars bn in the USA. The predicted increases in the elderly and immune-deficient populations will make influenza an even greater threat in the future. Despite the availability of vaccines, they have been least effective in these high-risk populations. Coupled with the requirement for routine revaccination, the need for effective antiviral agents is illustrated. The currently approved drugs, amantadine, rimantadine and ribavirin (in some countries), have limitations. They are only inhibitory against influenza A viruses, are prone to adverse reactions and quickly give rise to resistant virus. This review examines current drug therapies, antivirals in development and possible future opportunities for anti-influenza drugs.     

Combating influenza with antiviral therapy in the pediatric population

Influenza viruses are accountable for annual epidemics worldwide that result in significant morbidity and mortality. In preschool and school-aged children, prospective surveillance of influenza demonstrates yearly infection rates of 15-42%. Children can easily transmit the virus to other children, to employees in day-care and school settings, and to family members. Two classes of antiviral drugs, the adamantine derivatives (amantadine, rimantadine) and neuraminidase inhibitors (zanamivir and oseltamivir), have been approved for treatment and prophylaxis of influenza in the pediatric population. Duration of clinical symptoms decreases and daily activities are resumed sooner when therapy is begun within 48 hours of the onset of influenza symptoms. Mechanism of action, adverse effects, and development of resistant variants differ between the two drug classes. To our knowledge, head-to-head clinical trials between the classes and involving the neuraminidase inhibitors are nonexistent. Antiviral agents do not replace the annual influenza vaccine, and clinical trials indicate that amantadine, rimantadine, zanamivir, and oseltamivir are safe and effective for administration in the pediatric population.     

Recent progress and challenges in the computer-aided design of inhibitors for influenza A M2 channel proteins

The M2 channel protein has become an attractive target for the design of new drugs against influenza because it plays a crucial role in the replication cycle of influenza A virus. Several adamantane-based drugs have recently been developed to inhibit the activity of the M2 channel and overcome the drug resistance issues observed in amantadine and rimantadine. Computer-aided drug design continues to play a critical role in the drug discovery process in terms of its contribution to the identification and development of new therapeutic agents. Scientists working in this field are currently facing significant challenges with regard to creating novel platforms capable of enhancing our understanding of these proteins, with computational techniques being used to search for new potential drugs against influenza. This review provides a summary of recent progress in drug discovery toward the development therapeutic agents targeting M2 channel proteins. It is hoped that this review will stimulate the development of new strategies for overcoming drug resistance problems and encourage the design of new and improved drugs against influenza A virus.     

Respiratory viral infections in the elderly

Viral respiratory infections represent a significant challenge for those interested in improving the health of the elderly. Influenza continues to result in a large burden of excess morbidity and mortality. Two effective measures, inactivated influenza vaccine, and the antiviral drugs rimantadine and amantadine, are currently available for control of this disease. Inactivated vaccine should be given yearly to all of those over the age of 65, as well as younger individuals with high-risk medical conditions and individuals delivering care to such persons. Live, intranasally administered attenuated influenza vaccines are also in development, and may be useful in combination with inactivated vaccine in the elderly. The antiviral drugs amantadine and rimantadine are effective in the treatment and prevention of influenza A, although rimantadine is associated with fewer side-effects. Recently, the inhaled neuraminidase inhibitor zanamivir, which is active against both influenza A and B viruses, was licensed for use in uncomplicated influenza. The role of this drug in treatment and prevention of influenza in the elderly remains to be determined. Additional neuraminidase inhibitors are also being developed. In addition, to influenza, respiratory infections with respiratory syncytial virus, parainfluenza virus, rhinovirus, and coronavirus have been identified as potential problems in the elderly. With increasing attention, it is probable that the impact of these infections in this age group will be more extensively documented. Understanding of the immunology and pathogenesis of these infections in elderly adults is in its infancy, and considerable additional work will need to be performed towards development of effective control measures.     

Influenza

The currently available antiviral drugs rimantadine and amantadine are effective only for influenza A viruses. Another class of influenza antiviral drugs is the neuraminidase inhibitors, which selectively inhibit both influenza A and B viruses. Recent studies have found the neuraminidase inhibitors zanamivir and oseltamivir to be 67 - 82% effective in preventing laboratory-confirmed infection when administered as prophylaxis during the influenza season. As treatment, they reduce the duration of illness by 1 - 1.5 days when started within 36 - 48 h of illness onset. The reported adverse effects of these drugs are minimal, and unlike amantadine and rimantadine, the drugs do not appear to affect the central nervous system. Poor oral bioavailability and rapid renal clearance limit the use of zanamivir to inhalation and concern has been raised about its use in asthmatics. The sialic acid analogue, GS4071, has been shown to be a potent inhibitor of neuraminidase activity and is shown to be effective in controlling influenza, and its prodrug form - GS4104 (oseltamivir) can be given orally. Direct comparison of zanamivir and oseltamivir, their use for prophylaxis and treatment in high-risk groups, and evaluation of their cost effectiveness are all required before they enter routine clinical practice.     

Current and future antiviral therapy of severe seasonal and avian influenza

The currently circulating H3N2 and H1N1 subtypes of influenza A virus cause a transient, febrile upper respiratory illness in most adults and children ("seasonal influenza"), but infants, the elderly, immunodeficient and chronically ill persons may develop life-threatening primary viral pneumonia or complications such as bacterial pneumonia. By contrast, avian influenza viruses such as the H5N1 virus that recently emerged in Southeast Asia can cause severe disease when transferred from domestic poultry to previously healthy people ("avian influenza"). Most H5N1 patients present with fever, cough and shortness of breath that progress rapidly to adult respiratory distress syndrome. In seasonal influenza, viral replication remains confined to the respiratory tract, but limited studies indicate that H5N1 infections are characterized by systemic viral dissemination, high cytokine levels and multiorgan failure. Gastrointestinal infection and encephalitis also occur. The licensed anti-influenza drugs (the M2 ion channel blockers, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir) are beneficial for uncomplicated seasonal influenza, but appropriate dosing regimens for severe seasonal or H5N1 viral infections have not been defined. Treatment options may be limited by the rapid emergence of drug-resistant viruses. Ribavirin has also been used to a limited extent to treat influenza. This article reviews licensed drugs and treatments under development, including high-dose oseltamivir; parenterally administered neuraminidase inhibitors, peramivir and zanamivir; dimeric forms of zanamivir; the RNA polymerase inhibitor T-705; a ribavirin prodrug, viramidine; polyvalent and monoclonal antibodies; and combination therapies.     

Influenza

The currently available antiviral drugs rimantadine and amantadine are effective only for influenza A viruses. Another class of influenza antiviral drugs is the neuraminidase inhibitors, which selectively inhibit both influenza A and B viruses. Recent studies have found the neuraminidase inhibitors zanamivir and oseltamivir to be 67-82% effective in preventing laboratory-confirmed infection when administered as prophylaxis during the influenza season. As treatment, they reduce the duration of illness by 1-1.5 days when started within 36-48 h of illness onset. The reported adverse effects of these drugs are minimal, and unlike amantadine and rimantadine, the drugs do not appear to affect the central nervous system. Poor oral bioavailability and rapid renal clearance limit the use of zanamivir to inhalation and concern has been raised about its use in asthmatics. The sialic acid analogue, GS4071, has been shown to be a potent inhibitor of neuraminidase activity and is shown to be effective in controlling influenza, and its prodrug form--GS4104 (oseltamivir) can be given orally. Direct comparison of zanamivir and oseltamivir, their use for prophylaxis and treatment in high-risk groups, and evaluation of their cost effectiveness are all required before they enter routine clinical practice.     

Influenza viruses: basic biology and potential drug targets

Influenza A and influenza B viruses are continuing causes of morbidity and mortality on an annual basis. Influenza A viruses have historically caused periodic pandemics in the human population, sometimes with devastating consequences, such as in 1918. Fears of a new pandemic have increased in recent years because of continuing outbreaks of highly pathogenic H5N1 avian influenza viruses in birds with occasional, but often lethal infection of humans. Despite their importance as human pathogens, the antiviral drugs approved to treat influenza virus infections are currently limited to two targets, the viral neuraminidase and the viral ion channel, M2. The use of the M2 inhibitors amantadine and rimantadine is further limited by the propensity of these drugs to select for drug resistant variants. However, the replication cycle of influenza viruses has been intensively studied and is receiving increased attention. New opportunities exist to develop novel antiviral strategies targeting these viruses.     

Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes

Since 2003, highly pathogenic A(H5N1) influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. A group of 55 influenza A(H5N1) viruses isolated from various regions of South East Asia between 2004 and 2006 were tested for their susceptibility to the anti-influenza drugs the neuraminidase inhibitors and adamantanes. The majority of strains were found to be fully sensitive to the neuraminidase inhibitors oseltamivir carboxylate, zanamivir and peramivir; however two strains demonstrated increased IC50 values. Sequence analysis of these strains revealed mutations in the normally highly conserved residues 116 and 117 of the N1 neuraminidase. Sequence analysis of the M2 gene showed that all of the A(H5N1) viruses from Vietnam, Malaysia and Cambodia contained mutations (L26I and S31N) associated with resistance to the adamantane drugs (rimantadine and amantadine), while strains from Indonesia were found to be a mix of both adamantane resistant (S31N) and sensitive viruses. None of the A(H5N1) viruses from Myanmar contained mutations known to confer adamantane resistance. These results support the use of neuraminidase inhibitors as the most appropriate class of antiviral drug to prevent or treat human A(H5N1) virus infections.     

Influenza vaccination and antiviral therapy: is there a role for concurrent administration in the institutionalised elderly?

Influenza vaccination is estimated to be 50-68% efficacious in preventing pneumonia, hospitalisation or death in nursing home residents. Large culture-proven outbreaks may occur despite high resident vaccination rates. There is, therefore, a significant role for concurrent administration of influenza vaccination and antiviral therapy. The use of antiviral treatment and chemoprophylaxis requires community reporting of viral isolates, and contingency plans for rapid case identification and application of antiviral therapy. Clinicians must react quickly to control a highly infectious seasonal pathogen that may strike as an explosive outbreak. This situation is unique in geriatric practice. Current antiviral treatment should be administered within 48 hours of symptom onset, and is more efficacious if administered within 12 hours. In the case of an explosive institutional outbreak, a 1-day delay in prophylaxis may allow infection of many residents with a potentially fatal illness. Influenza must be differentiated from other respiratory viruses or syndromes. Grouped rapid diagnostic tests can aid laboratory confirmation. Antiviral agents include the M(2) inhibitors, amantadine and rimantadine, active against influenza A, and the neuraminidase inhibitors, zanamivir and oseltamivir, active against influenza A and B. In our experience, influenza B illness is as severe as influenza A. All agents have similar efficacy as treatment and prophylaxis against sensitive strains. When M(2) inhibitors are used simultaneously within an enclosed space (i.e. household or nursing home) as both treatment and prophylaxis, resistant strains may emerge that limit prophylactic efficacy. When M(2) inhibitors are administered to suspected cases (residents or staff) in institutions, precautions against secretion are especially important to diminish the risk of transmission of resistant virus. Rimantadine has been shown to have significantly fewer CNS adverse events compared with amantadine. Amantadine and oseltamivir require dosage adjustment in those with renal impairment. Oseltamivir, rimantadine and amantadine are administered by mouth, while zanamivir is administered by oral inhalation in a lactose powder. The labelling advises caution in the use of zanamivir in those with underlying airway disease. Pooled analysis of studies in patients given zanamivir indicate that individuals over the age of 50 years (at high risk for complications) and those severely symptomatic at presentation, tend to benefit most from early treatment. Neuraminidase inhibitors also diminish the need for antibacterials to treat secondary complications. An institutional programme to control influenza should include vaccination, and contingency plans for clinical surveillance, specimen processing and the rapid application of antiviral treatment and prophylaxis.     

Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants

Rapid development of resistant influenza variants after amantadine treatment is one of the main drawbacks of M2 blockers. On the other hand, the emergence of variants with low susceptibility to the neuraminidase (NA) inhibitors is limited. In the present study we examined whether combination therapy with two classes of anti-influenza drugs can affect the emergence of resistant variants in vitro. We observed that virus yields of human A/Nanchang/1/99 (H1N1), A/Panama/2007/99 (H3N2), and A/Hong Kong/156/97 (H5N1) viruses in MDCK cells were significantly reduced (P < 0.005) when the cells were treated with the combination of amantadine and low doses of oseltamivir carboxylate (≤1 μM). After five sequential passages in MDCK cells, the M2 protein of viruses cultivated with amantadine alone mutated at positions V27A and S31N/I. Viruses cultivated with oseltamivir carboxylate (≥0.001 μM) possessed mutations in the hemagglutinin (HA) protein. These variants showed reduced efficiency of binding to sialic acid receptors and decreased sensitivity to NA inhibitor in plaque reduction assay. Importantly, no mutations in the HA, NA, and M2 proteins were detected when the drugs were used in combination. Our results suggest that combination chemotherapy with M2 blocker and NA inhibitor reduced the emergence of drug-resistant influenza variants in vitro. This strategy could be an option for the control of influenza virus infection, and combinations with other novel drugs should be explored.     

Protective effects of phillyrin against influenza A virus in vivo

Influenza A virus infection represents a great threat to public health. However, owing to side effects and the emergence of resistant virus strains, the use of currently available anti-influenza drugs may be limited. In order to identify novel anti-influenza drugs, we investigated the antiviral effects of phillyrin against influenza A virus infection in vivo. The mean survival time, lung index, viral titers, influenza hemagglutinin (HA) protein and serum cytokines levels, and histopathological changes in lung tissue were examined. Administration of phillyrin at a dose of 20 mg/kg/day for 3 days significantly prolonged the mean survival time, reduced the lung index, decreased the virus titers and interleukin-6 levels, reduced the expression of HA, and attenuated lung tissue damage in mice infected with influenza A virus. Taken together, these data showed that phillyrin had potential protective effects against infection caused by influenza A virus.     

Antivirals for influenza: what is their role in the older patient?

Influenza infection is a cause of high morbidity and mortality in the elderly living in the community or in long-term care facilities. Yearly immunisation is the most important means for prevention of infection. However, protection by vaccination in the elderly is incomplete, and influenza infections and outbreaks in long-term care facilities still occur. Symptoms of influenza include fever, chills, headache, myalgia and respiratory symptoms. These clinical features overlap considerably with other co-circulating respiratory viruses such as respiratory syncytial virus and parainfluenza virus. Elderly and debilitated patients with influenza may present with less prominent respiratory symptoms and may present only with fever, lassitude and confusion. Antiviral prophylaxis and treatment with amantadine and rimantadine have been given in the past but adverse effects and early development of drug resistance have limited their use. The newer antivirals zanamivir and oseltamivir are equally effective and have the advantage of being well tolerated and active against both influenza A and B without the development of resistance. However, they are costly. Early identification and diagnosis of influenza illnesses are crucial since treatment with antiviral agents should be started within 48 hours of the beginning of illness.     

Measures for control of influenza

Influenza viruses cause recurring illnesses among individuals and recurring epidemics among populations. The major effective control measure for preventing infection and illness is inactivated vaccine, which can prevent influenza illnesses and their complications when given before exposure to the virus. While inactivated vaccine is effective for preventing influenza in most individuals, recommendations for its use focus on the prevention of severe disease and death among those who are at high risk of complications. Live attenuated cold-adapted influenza vaccines are nearing availability. They are given by nasal spray and are particularly effective for preventing influenza among young children, but also for preventing influenza among young adults, and enhancing protection against influenza when given with inactivated vaccine to elderly persons. The antiviral agents amantadine and rimantadine are related compounds that are effective for the prevention and treatment of influenza A virus infections and illnesses. Disadvantages are the rapid development of resistance during treatment and CNS adverse effects with amantadine. These drugs are also effective for outbreak control. Ribavirin is an antiviral given by small particle aerosol that is approved for the treatment of respiratory syncytial virus disease; it is also effective for the treatment of influenza. Two new antiviral agents inhibit influenza viral neuraminidase activity; one is given by inhalation or intranasally (zanamivir) and the other orally (GS4104). The former is free of adverse effects, while the latter induces nausea and vomiting in some individuals. Both are effective for the prevention as well as the treatment of influenza A and B illnesses. Thus, various measures for preventing and treating influenza are nearing availability. Their optimal use should further improve the control of influenza in individuals and populations as well as permit efforts to prevent community epidemics.     

Oseltamivir: a clinical and pharmacological perspective

Oseltamivir is the ethyl ester prodrug of the antiviral molecule, oseltamivir carboxylate, a potent and selective inhibitor of influenza A and B neuraminidase (NA) (sialidase). It is highly bioavailable in capsule and suspension formulations and, after conversion to the active metabolite in the liver, distributes throughout the body, including the upper and lower respiratory tract. Oseltamivir carboxylate is 3% bound to human plasma proteins and eliminated through the kidneys by a first-order process as unchanged drug by glomerular filtration and tubular secretion by an anionic transporter system. Given these characteristics, its potential for adverse interactions with other drugs appears limited to those arising from competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter. The terminal plasma elimination half-life is 1.8 h in healthy adults. Renal clearance is inversely related to renal function and averages 23 h after oral administration in individuals with creatinine clearance < 30 ml/min. In vitro studies have demonstrated potent antiviral activity against all strains of influenza A and B tested including avian H5N1 and H9N2 strains recently implicated in human cases in Hong Kong. Studies of both experimental and naturally-occurring influenza in humans have demonstrated efficacy in both the prevention and treatment of influenza A and B infection. The drug is well-tolerated with the only clinically important side effect being mild gastrointestinal upset. Resistance has been uncommonly seen after clinical use; the highest incidence was 5.5% in children treated for influenza A infection for 5 days. Viruses that develop resistance appear to be less virulent in laboratory animals and to replicate less efficiently than parent strains. Although oseltamivir and the M2 ion channel inhibitors, amantadine and rimantadine, have not been directly compared in clinical trials, the greater breadth of spectrum of oseltamivir, its modest side effect profile compared to amantadine and its lesser propensity to engender the emergence of transmissible drug-resistant strains all suggest strongly that oseltamivir is a significant new agent for the prevention and treatment of influenza. A series of controlled trials comparing M2 ion channel inhibitor drugs and the new neuraminidase (NA) inhibitor agents are now needed to test this hypothesis and thereby to further advance the science of antiviral drug use to control influenza.     

Neuraminidase inhibitors for the treatment and prevention of influenza

The impact of influenza virus infection is estimated to run into billions of dollars worldwide. Vaccination plays a key role in prevention; however, vaccines do not provide complete protection against influenza due to the constant mutation of the virus responsible. Unlike amantadine and rimantadine, which are only effective against influenza A, the new neuraminidase inhibitors zanamivir (Relenza), GlaxoSmithKline) and oseltamivir (Tamiflu), Gilead/Roche) are potent and specific inhibitors of influenza types A and B and have minimal side effects. The greatest benefit is derived if treatment commences as soon as possible after symptoms develop. In order for these inhibitors to have a significant impact on the disease, clinicians and the general public need to be made more aware of the symptoms of influenza and the availability of these new drugs.