Influenza chemotherapy:: a review of the present state of art and of new drugs in development

Influenza is worldwide one of the deadliest infectious diseases. Lethal influenza mutants can unpredictably arise, as in the 1918 pandemic, or in the 1997 I-long Kong influenza outbreak. Vaccines are today the only protective prophylactic agents, and development of potent new anti-influenza drugs of therapeutic effectiveness appears urgent. It is the aim of the present review, to summarize and discuss the different investigational approaches to this goal. In Medline- and several internet virology database-searches, numerous citations were compiled, and selected according to their relevance to the different topics discussed. The antiviral agents are classified according to their target in the viral replication cycle: proteolytic activation of haemagglutinin, attachment of the virus to specific cell-surface receptors, endocytosis and fusion with the endosomal membrane, uncoating of the nucleocapsid, multiplication, i.e. synthesis of viral RNA and mRNA, and release of the new virus generation from the host cell surface. Potential drugs, directed towards each of these replication steps are described with respect to their mechanism of action, antiviral activity, toxic side effects and induction of resistance. The most promising candidates for safe and potent new influenza drugs, are antiviral agents, directed towards a virus-specific, well conserved target, such as inhibitors of virus-cell fusion, inhibitors of RNA transcriptase and endonuclease, and inhibitors of neuraminidase. It can be hoped that in the near future potent and therapeutically effective anti-influenza drugs will be available. influenza belongs to the class of Orthomyxoviridae. Three subtypes of influenza viruses (A. B and C) are distinguished, influenza A being the most common source of epidemics or pandemics: this subtype can affect humans, other mammalian and avian species, and is genetically extremely variable (antigenic shifts or drifts). By reassortment of genes during virus replication- either with other human influenza virus types or with avian or swine virus genetic material, new reassortant virus strains are produced [30, 35, 65, 74]. The resulting new virus strain is not recognized by the human immune system, and may cause unpredictable and severe epidemic or even pandemic influenza outbreaks. The most lethal pandemic of 1918 (with over 20 millions of deaths) was followed by several more recent influenza epidemics [15, 19, 22, 57], all clearly associated with the appearance of new influenza A strains. Ln the 1997 Hong Kong influenza outbreak, the appearance of an avian (H5N1) virus was - for the first time - observed in humans [9]. In an attempt to control and prevent highly lethal pandemics, a global program for influenza surveillance was initiated by the World Health Organization (WHO) in 1947. Epidemics spread rapidly from country to country, in some cases with alarming speed: one to six months for the 1968 Hong Kong- and the Russian flu of 1977, respectively [15]. Due to increased global traveling and trading, this spread can be expected to be even faster in the future. In a moderate influenza year, globally as many as 500 million people are affected by the disease, and annually 20-40 000 deadly flu infections were registered in the US [19]. Despite these facts, influenza appears to be an underestimated public health problem, and HIV remains the predominant target for antiviral research [3].