Targeting both the hydrophobic pocket and N-terminus of HIV-1 nucleocapsid protein 7: synthesis and optimization of new antiretroviral compounds.

During the past 25 years, the arsenal of drugs to combat HIV-1 infection has increased continuously, even though most anti-HIV-1 drugs experienced clinical failure due to antiretroviral drug resistance resulting from mutations in HIV-1 protein targets. Therefore, a medical need in this field is still felt, and additional conserved drug targets need to be explored to achieve virus suppression in drug-experienced patients or patients infected with drug-resistant viruses. In this context, the Nucleocapsid protein 7 (NCp7) is considered a strongly profitable drug target as it is a highly conserved protein in several HIV-1 subtypes that plays a central role in virus replication, and whose inhibition could interfere with multiple steps in the HIV-1 life, a unique property not shown by any of the other antiretroviral classes. This PhD thesis has been devoted to the discovery and synthesis of NCp7 inhibitors characterized by a bifunctionalized structure with the aim to block two binding sites within NCp7. The first synthetic efforts were addressed to the development of an easy and reproducible synthetic pathway for obtaining desired products which could then be applied for the synthesis of derivatives. All compounds were tested for their antiviral activity as well as for NCp7 inhibition. Results showed that this class of compounds displays a very interesting profile. The second part of the work focused on the preparation and characterization of a liposomal formulation of a selected compound as drug delivery system with the aim to improve its pharmacokinetic profile.