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 Hong 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.