Antiviral drugs development

Humans, plants, insects, and other animals are all susceptible to viral infection therefore, prevention and control of viral disease carry important health and economic implications. The common cold, acquired immune deficiency syndrome (AIDS), and some cancers are carried by viruses. Viral plant diseases are known to impact fruit trees, tobacco, and many vegetables [1]. Both insects and animals have the ability to transfer viral disease to humans and other animals. The health and economic consequences of viral disease carry enormous consequences, and significant advances have been made toward amelioration of antiviral threats. There is a critical need to identify novel drug classes and new chemical structures, which can be exploited for antiviral drug development. 

Rationale for the Selection of HCV NS3 Helicase as a Target for Antiviral Drug Development... 

A Novel Target in Antiviral Drug Development and Basic In Vitro Assays with the Purified Enzyme... 

E. De Qercq, in E. De Qercq and R. T. Walker, eds., Antiviral Drug Development—A Multidisciplinary Approach Plenum Press, New York, 1987, pp. 97-122. 

Viruses are small infectious agents composed of a nucleic acid genome (DNA or RNA) encased by structural proteins and in some cases a lipid envelope. They are the causative agents of a number of human infectious diseases, the most important for public health today being acquired immunodeficiency syndrome (AIDS), hepatitis, influenza, measles, and vituses causing diarrhoea (e.g., rotavirus). In addition, certain viruses contribute to the development of cancer. Antiviral drugs inhibit viral replication by specifically targeting viral enzymes or functions and are used to treat specific virus-associated diseases. 

Patients receiving antiviral drugs for HIV infections may continue to develop opportunistic infectionsand other complications of HiV. The nurse monitors all patients closely for sgns of infection such as fever (even low-grade fever), malaise, sore throat, or lethargy. 

Table 1 Antiviral drugs in clinical use or in advanced stages of development (italics)...

The antiviral strategies discussed earlier as well as all antiviral drugs available to date are based on the principles of conventional chemotherapy. However, recent discoveries and developments in molecular biology have opened perspectives for alternative approaches of intervention. 

Fig. 3 Stepwise development of antiviral resistance. Because of the rapid mutation rate of viruses, the virus population before treatment (a) contains variants, which display by chance a low level of resistance to the drug (indicated by the darker hue). Treatment with suboptimal levels of an antiviral drug (b) creates a bottleneck, which selects for these variants (c). These can further replicate in the presence of the drug and thereby acquire additional mutations, leading to resistant variants with enhanced replicative fitness (d)...

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

Ealagas ME, Paya C, Ruthazer R, Badley A, Patel R, Wiesner R et al. (1998) Significance of cytomegalovirus for long-term survival after orthotopic liver transplantation a prospective derivation and validation cohort analysis. Transplantation 66 1020-1028 Field AK (1999) Human cytomegalovirus challenges, opportunities and new drug development. Antivir Chem Chemother 10 219-232... 

In this chapter we describe the current insights into the evolution of viruses under pressure of antiviral therapy and the potential impact on viral fimess. As most recent work in this field has been done in the field of human immunodeficiency virus (HIV), we use the evolution of this virus as the basis for the chapter. Subsequently, we describe resistance evolution for Hepatitis B virus (HBV), where large progress has been made in recent years. Furthermore, we describe the resistance development for Hepatitis C virus (HCV), for which a very active drug development program is undertaken by several pharmaceutical companies. Finally, we discuss resistance evolution for Influenza. 

HavUr DV, Richman DD (1996) Viral dynamics of HIV implications for drug development and therapeutic strategies. Ann Intern Med 124(11) 984—994 Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Foms X, Erhardt A, Cronlein J, Chaves RL, Yong CL, Nehmiz G, Steinmann GG (2004) Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype I patients. Gastroenterology 127(5) 1347-1355... 

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. 

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