Final Report Summary - ANTIVIRAL (Design, synthesis and biological evaluation of HIV-1 and HCV inhibitors) The objectives of the project 'ANTIVIRAL' were the discovery of inhibitors to treat human immunodeficiency virus type one (HIV-1) and hepatitis-C (HCV). The objectives of the project were later amended to include the design of inhibitors for the treatment of cancer as well. Thus the first part of the project, for the period between 3 September 2007 and 2 September 2009, included an in-depth investigation of HIV-1 and HCV inhibitors, by employing both computational and genetic analyses. Based on our results we were able to provide an explanation on the resistance pathways that are observed for Raltegravir, the first Food and Drug Administration (FDA) approved HIV-1 integrase (IN) inhibitor. Furthermore, through exploratory data analyses of HIV-1 IN inhibitors, we derived a correlation between IC50 values, binding energy and compound hydrophobicity, as characterised by cLogP. The first part of the project was carried out under the scientific supervision of Prof. L. Kostrikis at the University of Cyprus. The second part of project covering the period from 1 May 2011 to 14 January 2013 included the computer-aided design of new compounds for the treatment of cancer whose structure is inspired by natural products. Natural products are organic molecules found in nature, i.e. animals, plants and microorganisms that often exhibit activity against human diseases. Currently, there are at least 40 natural products and derivatives in clinical use and dozens under clinical development. Natural products have shown an excellent track record for the treatment of cancer and have been used clinically since the early 1960s. In this project, we wished to use nature as a source of inspiration for designing new inhibitors that may potentially exhibit better activity and higher selectivity. For the design of the new inhibitors we followed a computer-aided approach that involved docking of the natural product at the active site of its target protein, analysis of the best docked conformations and design of new analogues with better binding parameters to the protein. During the course of this project we identified a family of natural products, the argyrins, as promising compounds for drug development. Argyrin A is a potent antitumoural drug whose activity depends on the prevention of the cyclin kinase inhibitor p27kip1 destruction, as reduction in the cellular levels of p27kip1 is frequently found in human cancers. Argyrin A exerts its effects through direct inhibition of the proteasome. Proteasomes recognise and digest protein substrates that have been marked for degradation by the attachment of an ubiquitin moiety. Owing to their broad involvement in many cellular processes, proteasomes play a key role in many diseases, including cancer. Inhibitors of the proteasome have to be highly selective and preferably exhibit subunit specificity by inhibiting one or two of the three active sites of the proteasome. Currently, there are two FDA approved proteasome inhibitors for the treatment of cancer, bortezomib a small molecule inhibitor and carfilzomib, which is a derivative of the natural product epoxomycin. Argyrin A is a potent inhibitor of the proteasome that binds non-selectively to the three active sites. In this project we wished to design new argyrin-based analogues as potent inhibitors of the proteasome that would exhibit subunit specificity. As such we prepared a three-dimensional (3D) 'humanised' model of the 20S proteasome, which we used to perform molecular docking experiments of argyrin A and analogues. We performed an in-depth analysis of the binding conformation and binding site interactions of argyrin A to the three active sites ß1, ß2 and ß5. We designed new argyrin analogues that selectively exhibit better binding toward the ß1 binding pocket, as compared to the ß2 and ß5. The potential impact of these results would be on the successful development of drugs to treat HIV-1, HCV and cancer. HIV and HCV are two of the major causes of death in third world countries. Furthermore, inhibitors of the proteasome are used for the treatment of cancer a potentially terminal disease that affects one in every three people worldwide. Currently, there is no cure for cancer but there are treatment options that became available through research, which aim to increase the lifespan and quality of life of people suffering from cancer. Documenti correlati Final Report - ANTIVIRAL (Design, synthesis and biological evaluation of HIV-1 and HCV inhibitors)
