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.
Leishmaniasis-HIV co-infection, first observed in the mid-1980s, has appeared in 1/3 of the endemic countries and has been reported in 35 endemic countries. The areas of co-infection diffusion mainly include southern Europe, middle Africa and south America. Number of new cases is rising where there is limited access to the highly active anti-retroviral therapy (HAART). By 2001, a total of 1911 co-infection cases had been reported. Leishmaniasis is more likely to develop in HIV-infected patients (enhanced risk by 100 to 2.320 times in areas of endemicity) and impairs their response to antiretroviral treatment. Moreover, co-infection diagnosis can be difficult.
Leishmaniasis and malaria are the two major life-threatening parasitic diseases. Malaria is widespread in tropical and subtropical regions where it accounts for more than 250 million cases annually while 2 million new cases of leishmaniasis are diagnosed every year. Because of geographical overlap, leishmaniasis and malaria co-infections are extremely common, although under-studied and under-diagnosed. The risk of co-infection is particularly high for children and women in endemic countries.
Malaria and HIV are two of the most deadly diseases in Africa. HIV-related immunosuppression is correlated with increased malaria infection, burden, treatment failure, and with complicated malaria. Malaria increases the viral load in HIV patients (by an order of magnitude), with pregnant women particularly affected. The use of HAART and antimalarials in combination therapies, raise concerns regarding synergistic and antagonistic effects on efficacy, toxicity and drug-drug interactions. Particularly vulnerable are population from diseases endemic countries where monitoring and management are complicated. Therefore, a single administration should be favoured over multiple one.
The combination of multiple drugs in a therapeutic regimen (i.e. combination therapy) has been proposed recently for co-infections. The impact of the project will be the production of a new engineered compound for curing one or more co-infections caused by leishmaniasis/malaria/AIDS, new lead compounds for curing the single infections in infected animal model, societal impact related on higher accessibility, suitability and sustainability in co-infections therapy. Thus, the most suitable drug for conjugation/combination will be studied at the beginning of the project.
The overall methodology and associated work plan of the project proposal starts from a methodological approach aimed to develop new drug leads (conjugates and/or to be used in combination) as innovative therapeutic strategy for the treatment of co-infections through successive rounds of Cyclic Process for Drug Development (CPDD). The drug discovery process starts from the identification of leads and their biological properties definition, then a lead optimization process to achieve a conjugate molecular hybrid composed of the drug lead against one of the infections and a drug in therapy against the second infection. The lead identification will be achieved through phenotypic screening, drug repurposing and target-based screening. The lead optimization process will rely on a multidisciplinary approach involving design and synthesis, enzymatic assays, in vitro evaluation, early toxicity studies and PK-ADME evaluation in animal models.
The conjugate lead compound developed during the present project expected to be active can be effective with the following properties grouped in the TPP: no induction of mitochondria or inhibition that may affect drug stability, effective in combination with known drugs against other infections, potential conjugation with other drugs used in other infections, no synergic toxicity, potential activity against more infections alone, effective as single agent against the targeted infections.
In the view of above, Linking-Acts will largely contribute to the advancement of knowledge with respect to the state of the art. In particular, this project will lead to the discovery of at least one novel drug combination as conjugated or non-conjugated drug lead with favourable PK on healthy mice model and new optimized drug leads for further combination will be developed. Therefore, our strategy of drug combination will furnish new conjugated compounds following the polypharmacology concept for at least one of the three type of co-infections or possibly for each co-infection. Moreover, new chemical entities will be patented and new publications will be submitted depending on the results.