Editorial [Hot Topic: New Approaches to the Treatment of Viral Diseases (Guest Editor: Cristina Gardelli)]

Epidemiological figures indicate that today 40 million people are living with HIV/AIDS including 2.3 million children. 170 million people worldwide are infected with hepatitis C (HCV) virus, with this being the second most common etiological agent of chronic liver disease and hepatocellular carcinoma. The four reviews in this issue discuss the most recent approaches towards the care of these two types of viral diseases. The first two contributions are dedicated to the most recent strategies in the fight against AIDS. June 2006 marked the 25th anniversary of the discovery of HIV/AIDS and since that fateful report on the 5th June 1981, this disease has claimed the lives of over 25 million people worldwide and it has afflicted every corner of the world crossing geographic, cultural, ethnic and socioeconomic boundaries. Currently, the therapy for AIDS relies on drugs with three mechanisms: HIV protease, HIV reverse transcriptase nucleoside and non nucleoside inhibitors. Unfortunately the ability of the virus to mutate and become resistant to these treatments has led to an increasing proportion of the infected population harboring virus that is resistant to these classes of drugs. In this issue the most promising scientific findings about the discovery of two new classes of drugs will be presented: Melissa S. Egbertson summarizes some of the developments in Merck Laboratories on HIV Integrase Inhibitors and Claudiu Supuran and coauthors illustrate the most recent progress in the development of HIV entry inhibitors. Melissa Egbertson describes efforts in the exploration of Integrase activity and the design of potent and efficacious inhibitors of HIV Integrase. An important step in the evolution of the HIV Integrase program at Merck was the development of a biochemical assay separating the final strand transfer step from the earlier assembly and processing step; using this assay, compounds were screened for their ability to act solely as inhibitors of strand transfer. The evolution from the diketoacid scaffold to the 1,6-naphthyridine template is reported and the optimization route, towards compounds selected for further preclinical evaluation, is described. Claudiu T. Supuran and coauthors review the recent developments in the field of HIV entry inhibitors. Viral entry into the cell takes place in three steps: attachment of the virus to the host cell through the formation of a complex between the trimeric gp120-gp41 viral glycoproteins, the CD4 receptor and the chemokine coreceptor (CCR5 or CXCR4); interaction of the virus with the co-receptors and fusion of the virus and host cell membranes. All three steps have been considered for the design of HIV entry inhibitors and these different types of agents have been reviewed by the authors. They also underline the potential interference of these compounds with homeostasis of the immune system and the possible risk of inducing or shutting off inflammatory pathways. A careful design to achieve selectivity over the host receptors is considered of fundamental importance for the success of these agents. The third and the fourth contributions are dedicated to the efforts towards a therapy for Hepatitis C. Hepatitis C is currently treated with PEGylated α-interferon alone or in combination with ribavirin and no vaccine is available. Up to 80% of genotype- 2 infected patients respond to interferon therapy whereas only about 50% of genotype-1 infected people show a sustained response. In recent years drug development efforts have mainly been directed at targeting inhibition of two viral enzymes: NS3 protease and NS5B RNA dependent RNA polymerase.