http://www.ddtjournal.com Review Drug Discov Ther 2007;1(1):14-22. ABSTRACT: Viral diseases, such as acquired immunodeficiency syndrome (AIDS), respiratory diseases, and hepatitis, are the leading causes of death in humans worldwide, despite the tremendous progress in human medicine. The lack of effective therapies and/or vaccines for several viral infections, and the rapid emergence of new drug-resistant viruses have urged a growing need for developing new and effective chemotherapeutic agents to treat viral diseases. Recent advances in the understanding of both the cellular and molecular mechanisms of virus replication have provided the basis for novel therapeutic strategies. Several hundred natural products have been isolated for screening and identifying antiviral activity, and some have been shown to have great medicinal value in preventing and/or ameliorating viral diseases in preclinical and clinical trials. There are innumerable potentially useful medicinal plants and herbs waiting to be evaluated and exploited for therapeutic applications against genetically and functionally diverse virus families. This review focuses on several selected pathogenic viruses, including the human immunodeficiency virus (HIV), influenza virus, hepatitis B and C viruses and herpes viruses, and antiviral natural compounds from medicinal plants (herbs), while paying particular attention to promising compounds in preclinical and clinical trials. We also focused our attention on the need to develop effective screening systems for antiviral activity. Key Words: HIV-1, influenza virus, HBV/HCV, HSV-1, HSV-2, antiviral, natural product, herbs, medicinal plant Introduction Viral diseases, caused by pathogenic virus infections which have high morbidity and mortality rates, are still the leading cause of death in humans worldwide. Although effective vaccines have led or might lead to the eradication of important viral pathogens, such as smallpox, polio, and mumps, other viral diseases, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), have proven difficult to combat using the conventional vaccine approach. Moreover, the emergence of viral resistance to drugs, as well as the serious adverse effects induced by antiviral drugs, has caused serious medical problems, particularly when administered in combination over prolonged treatment periods. Although many new antiviral drugs have been approved in recent years, most of them are used for the treatment of HIV, and these drugs are quite costly, thus limiting their use in developing countries, where infection is most prevalent. A virus is a unique pathogen which is incapable of replicating without a host cell. It utilizes the host cell environment and cellular factors for its propagation. This unique feature of viruses makes it difficult to design a treatment to attack the virus or its replication directly without any adverse effects on the infected cells. However, viruses share a common stage in their replication cycle, which includes attachment and entry to the host cell, transcription of viral mRNA, replication of viral genome, assembly and budding as progeny virus particles, regardless of different genetic materials (DNA or RNA), or whether has a different invasion strategy of which enveloped with a lipid-containing membrane (enveloped virus) or not. Whereas, viruses with an RNA genome, such as HIV, HCV, and influenza, are genetically highly variable, due to the fact that viral reverse transcriptase or RNA-dependent RNA polymerase lack a proofreading mechanism. Accumulated mutations in viral RNA genome have been proven to be associated with the emergence of drug-resistant viruses (1-3). The emergence of drug- Viral infectious disease and natural products with antiviral activity Kaio Kitazato 1 , Yifei Wang 2 , Nobuyuki Kobayashi 1, 3, * 1 Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; 2 Guangzhoujinan Biomedicine Research & Development Center, Jinan University, Guangzhou, China; 3 Central Research Center, AVSS. Co., 1-22 Wakaba-machi, Nagasaki, Japan. 14 *Correspondence to: Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo- machi, Nagasaki 852-8521, Japan; e-mail: nobnob@net.nagasaki-u.ac.jp Received June 25, 2007 Accepted July 1, 2007