Ricerc@Sapienza

Linking-Acts aims at the development of effective combinations of innovative drug leads with existing drugs to cure poverty related co-infections caused by Leishmania and Malaria parasites and HIV infections, through a polypharmacology approach. The available drugs are costly and often not available for those in need, therefore drug combination treating two or more diseases at the same time could be a sustainable solution. The combination treatments presently available show problems of suitable pharmacokinetics and toxicity, therefore our approach aims at overcoming the above issues. The goal of the project is to deliver one or more conjugated compounds between one known drug and the drug lead compounds to be effective against: AIDS-Leishmaniasis, AIDS-Malaria, Malaria-Leishmaniasis. The conjugated compounds will be selected on the basis of satisfactory pharmacokinetic and safety profile on healthy, non-infected mice. In doing this, a polypharmacology strategy will be adopted. The results will be achieved through a multidisciplinary approach integrated within a sequential process of drug-discovery. This process will start from the lead optimization process to achieve a conjugate compound, composed by the drug lead against one of the infections and a drug in therapy against the second infection. The conjugate should have a target product profile (TPP) suitable for the combination therapy. Main properties will be low toxicity, efficacy in cellular and animal model of the single infection and of the combination (with the exception of leads against HIV-1). In details, the methodologies adopted will be lead optimization and lead selection adopting different assays for early toxicity studies. Conjugation technologies studies will be carried out to have a panel of different potential linkers cleavable with different mechanisms. Compounds that will be identified as a good profile inhibitors will be tested in the healthy mouse model to evaluate the pharmacokinetic behaviour.