In the proposed study we aim to investigate novel Human Immunodeficiency Virus (HIV) and Hepatitis-C (HCV) inhibitors that will improve the quality of life of the infected patients, reduce or avoid the toxic effects of the current treatment and ultimately assist in the eradication of these viruses. The current treatment for HIV that includes inhibitors of viral entry, protease and transcriptase activity, is compromised by the persistence of viral reservoirs, drug resistance and adverse side effects. HIV-1 integrase (IN), the enzyme responsible for integrating the viral DNA to the host genome, is essential for viral replication and represents an ideal target for drug design. The current treatment for HCV of interferon-α and ribavirin has demonstrated limited success in treating all genotypes and alternatives with improved efficacy represent an important unmet need. The HCV NS2-3 and NS3-4A proteases and the NS5B RNA dependent RNA polymerase are an essential component of the viral maturation and replication and are thus, ideal targets for the development of new anti-HCV inhibitors. In the course of this project, we will explore the design of novel inhibitors that will target the viral enzyme IN, the HCV NS2-3, NS3-4A proteases and the NS5B RNA dependent RNA polymerase. In our study we will introduce state-of-the-art technologies; we intend to employ a de novo computer-aided drug design method for designing novel inhibitors of IN, NS2-3, NS3-4A and NS5B viral proteins, design synthetic routes for their preparation and develop specific assays for the aforementioned viral proteins. The creation of new medicine necessitates efforts in multiple directions and requires collaborations between research institutes, here the University of Cyprus (UC, host institute) and the Scripps Research Institute (TSRI). The proposed project is expected to enhance scientific excellence and competitiveness in the pharmaceutical sciences and innovative drug research carried out in the EU.