Structure-based drug discovery

1) CHARACTERIZATION AND INHIBITION OF THE FLAVIVIRUS REPLICATION.
The comprehensive characterization and inhibition (with small molecules) of the RNA viruses replicative machinery through the structural and functional studies of the viral replication proteins.
Main aim of the project is to identify, through in silico docking and protein crystallography, molecules with inhibitory activity against DENV replication and, in a broad-spectrum, against flaviviruses other than DENV. Infections by these neurotropic viruses may result in life-threatening aseptic encephalitis, with high risk of life-long debilitating neurologic sequels, with an associated mortality of 2.5%. Currently no vaccines or specific antiviral agents are available to combat these pathogens. Target-based design of molecules against flaviviral enzymes may be a promising strategy towards the development of selective Flavivirus' inhibitors.
2) STRUCTURE-BASED DESIGN OF PRO-APOPTOTIC MOLECULES FOR CANCER THERAPY.
The study of the processes involved in various apoptotic pathways, through the analysis of the 3D structures of the proteins involved in the pathway, with the ultimate aim to design pro-apoptotic molecules for cancer therapy.
The genes for some IAPs (proteins of the inhibitor-of-apoptosis family) are known to be overexpressed in certain tumours. Indeed, IAP blocking compounds (Smac mimetics, SMs) based on the IAP antagonist Smac/Diablo are already being developed for the treatment of cancer. These antagonists target the bacuolavirus IAP Repeat (BIR) type II domain of IAPs such as XIAP (X-chromosome-linked IAP) and cIAP1/2 (cellular IAP1 and cellular IAP2), which inhibit apoptosis by different mechanisms. The project proposes a novel approach to interfering with the functions of XIAP and cIAP1/2, based on the development of protein-protein-interaction (PPI) inhibitors of the BIR1 (type I) domain of XIAP and cIAP2. The rational behind this approach is that the interaction of XIAP-BIR1 with TAB1 and that of cIAP2-BIR1 with TRAF2 lead to the formation of corresponding complex regulatory factors that drive the canonical pathway of NF-kappaB activation to inflamation and cell survival. The main aim of the project is, following drug design protocols, to identify and optimize compounds that can be used to control the supression of apoptosis by XIAP and/or cIAP regulators. If successful the project could have a very significant on understanding control of cancer cells and on cancer treatment.

Members:
Federica Cossu
Matteo De Rosa
Eloise Mastrangelo (Principal investigator)
Mario Milani