On the evolutionary scale, viruses are as old as their hosts, and reports or representations of viral diseases date back to ancient history. The awareness of viral pathogens increased in the last 500 years with deadly epidemics of smallpox and a large death toll taken by measles and influenza. A prime example for a devastating viral pandemic leaving little options for intervention is the so-called Spanish flu in 1918/1919, which demanded more victims than the entire world war I. Because of the genetic flexibility of viruses, new strains or species constantly emerge, the most prominent example being human immunodeficiency virus (HIV), the causative agent of AIDS, which was first identified in the early 80s of the twentieth century.

From the early 1900s on, hygiene measures greatly improved the containment of many infectious diseases. Furthermore, the discovery of antibiotics significantly increased the range of therapeutic options against bacterial diseases. These drugs target bacterial functions such as cell wall integrity, prokaryotic DNA replication, or protein expression. As obligate intracellular parasites, viruses heavily rely on host cell functions to achieve efficient replication and thus are not targeted by these drugs. A crucial discovery, by Enders, Weller, and Robbins in 1949, laying the ground for the development of antiviral drugs was the ability to cultivate cells in vitro and infect them with a virus (in this case poliovirus). The first antivirals were fortuitous discoveries of compounds originally developed for other purposes but inhibiting the replication of one or several viruses in tissue culture. Accordingly, their mechanisms of action were discovered significantly only later.

The advent of molecular biology greatly facilitated antiviral drug discovery in the past 30 years, with an unprecedented effort by both academic research and pharmaceutical industry, leading to approximately 25 HIV-specific drugs from various classes that are currently in clinical use. Similar drug development strategies are being pursued for treatment of hepatitis C, with first compounds reaching clinical application. Most antiviral drugs are targeting virus-encoded enzymes essential for viral replication and sufficiently different from their host counterparts to achieve acceptable toxicity (e.g., polymerases, proteases, endonucleases, sialidases, and helicases). More recent drug discovery approaches are directed against nonen-zymatic viral functions (e.g., fusion inhibitors) and cellular factors required for viral replication (e.g., coreceptor antagonists), and these are complemented by therapeutic approaches boosting the immune response against viral infection. Novel developments include small interfering (si) RNA approaches that may reach clinical use in topical applications (i.e., respiratory diseases), but may only achieve their full potential once gene therapy becomes a feasible option.

A crucial issue for antiviral therapy is the fact that all antiviral substances rapidly select for resistance; thus, monitoring and overcoming resistance has become a most important clinical paradigm of antiviral therapy. This calls for cautious use of antiviral drugs and implementation of combination therapies. In parallel, efforts in drug discovery have to be continued to develop compounds with novel mode-of-action and activity against resistant strains. This book reviews the current status of antiviral therapy, from the roads to development of new compounds to their clinical use and cost effectiveness. Individual chapters address in more detail all available drug classes and outline new approaches currently under development.

We thank the many authors for their contributions to produce this volume. As authors ourselves, we recognize the difficulties of working on a project of this nature. The fact that all authors were willing to accept changes in their chapters, especially the frequent reduction of length of drafts, facilitated our editorial efforts to a great extent. Furthermore, we thank Sandra Buhler, Antje Keppler, and Barbara Muller for critical reading of the manuscripts and their enormous help to adapt the drafts to the publisher's guidelines. We also thank Susanne Dathe, desk editor biomedicine at Springer, for her support and expert editorial help.

In conclusion, we hope that this volume will be valued by researchers in the field, and by those who are engaged in the future developments and applications of antiviral strategies.

Heidelberg, Germany

Hans-Georg Kräusslich Ralf Bartenschlager

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