Emerging trends and targets in antiviral drug discovery

The modern paradigm in antiviral drug discovery is exemplified by the therapy of AIDS: the success of HAART in the treatment of patients infected with HIV was made possible by the development of a considerable number of compounds targeted to specific steps of virus replication. The currently combined-therapy regimen exploits drugs aimed at HIV reverse transcriptase (NRTI and NNRTI) and protease (PI), but intensive research in genome sequencing, structural biology and structure-based drug design led to the discovery of newer molecules targeted to other and distinct steps in HIV replication. The “deceptive simplicity” (1) of HIV is in patent contrast with its ability to persistently infect humans: indeed current research regards also cellular targets exploited by the virus, such as the chemokine receptors CCR5 and CXCR4. Since toxicity and emergence of resistance can lead to failure of therapies, and the development of effective vaccines remains unachieved, AIDS treatment relies still on the search of newer viral targets for newer classes of drugs. Nef is an attractive target, exploited in high-throughput screening, as well as the RNase H activity of reverse transcriptase. Other emerging steps and targets in viral life cycle are the strand transfer events catalyzed by the viral nucleocapsid protein (NC) of HIV, a small basic protein that binds nucleic acids. RNA as a target for novel HIV-1 inhibitors largely proceeded through exploitation of the ligand-induced refolding of the transactivation response element TAR, or by the search of leads for the stem-loop element of Rev-responsible-element (RRE) in HIV. RNA elements are key players in the replication of other viruses, such as the IRES of hepatitis C (HCV): about 3% of worldwide population is affected by HCV, a chronic infection in the liver that eventually causes cirrhosis and hepatocellular carcinoma. HCV causes now more deaths per year than HIV-1 (2). The concern for this “silent pandemic” led to an intensive research on HCV in the last 10 years, culminating in the recent approval of HCV protease inhibitors. The conspicuous science advancements in HIV field have helped to shape HCV research: despite being different viruses, parallels in HIV and HCV life cycles were drawn (3). It is hoped that the “lessons learned” from HIV drug development could lead to rapid achievements in HCV drug discovery.