When two become one: the power of multifunctional drugs to combat deadly tropical infections

Tropical infections kill millions people worldwide each year, in particular in the developing world. However, drug companies are reluctant to develop innovative medicines for such diseases because the people affected are often poor and disadvantaged and cannot pay for novel but expensive products, meaning that there is no market for the pharmaceutical industry to exploit. At an academic level, where publication of research in academic journals rather than direct practical contribution to social good are rewarded, the gap between discovering a drug in the lab and using it in a patient has greatly widened. For these reasons, the drug ¡°pipeline¡± for these ¡°neglected diseases¡± is almost dry.

Examples of tropical infections are those caused by Trypanosoma and Leishmania parasites, which cause several lethal diseases. Trypanosoma species are responsible for Chagas¡¯ disease in South America and sleeping sickness in Africa, whereas Leishmania species are responsible for skin and organ infections endemic in 88 countries in the horn of Africa, South Asia, and Latin America. Overall, more than 100 million people worldwide are presently at risk from these diseases.

Because of their occurrence in low-income and middle-income countries, Trypanosoma and Leishmania infections do not have high visibility in Western societies, although Chagas¡¯ disease, sleeping sickness, and visceral leishmaniasis are the three neglected tropical diseases with the highest rates of death. For these reasons, the World Health Organization characterises them as the most challenging of the neglected tropical diseases.

Classic drug discovery strategies¡ªthat is, ¡°one disease, one target¡± and ¡°one compound, one target¡±¡ª have essentially failed when facing the multifactorial nature of parasitic diseases, because it¡¯s too quick and easy for the parasites to develop resistance to a single-target-directed agent.

To confront this issue, it has been proposed that combination therapy, namely a cocktail of drugs, could be used to treat patients infected by resistant parasites. Very recently, a drug combination has been developed for parasitic diseases¡ªthe new malaria drug ASAQ, which was launched by the French pharmaceutical giant sanofi-aventis and the not-for-profit entity Drugs for Neglected Diseases initiative (DNDi). Studies have shown that this new medicine may help confront multidrug resistancein the parasite Plasmodium falciparum, one of the species of Plasmodium that cause malaria in humans. Although promising, combination therapies involve patients taking a whole handful drugs each day, and many fail to do so.

However, an innovative strategy is emerging in drug discovery that might open up new avenues for the treatment of major parasitic diseases, namely developing a single chemical entity that is able to act simultaneously on several of the key pathways that are of importance for a parasite¡¯s survival. Such ¡°one compound, multiple targets¡± multifunctional drugs could have the same effect as combination therapy and could be better in terms of compliance, drug-drug interactions, and side effects. In fact, the clinical development of multifunctional molecules is, in principle, no different from the development of any other single molecule, and, therefore, less expensive. Plus, the number of pills and the dosage required is greatly simplified with multifunctional drugs compared with drug combinations.

Multifunctional drug candidates have already been developed for different conditions such as inflammation, schizophrenia, allergy, depression, hypertension, and metabolic diseases. In these cases, the capability of the drugs to act at several key points of disease generation and progression has provided medicines with superior clinical profiles. This approach has also very recently been applied in the field of neurodegenerative diseases and to develop innovative anti-cancer drug candidates. In the latter case, multifunctional drugs have added value because they might help to overcome acquired drug resistance, which is a major limitation for a successful treatment of cancer.

Given that the pharmaceutical industry has almost ceased all activities in the development of drugs against Trypanosoma and Leishmania diseases, present efforts rely nearly exclusively on laboratory research in the public sector, such as in universities. That¡¯s where my research comes in.

One of the main research lines in the Department of Pharmaceutical Sciences at the University of Bologna, where I work, is to discover novel, active, non-toxic, and readily affordable drug candidates to combat Trypanosoma and Leishmania diseases. Uniquely, we are exploiting an innovative approach to designing multifunctional compounds that we previously successfully applied to designing drugs for neurodegenerative diseases. A team composed of young researchers in the areas of computer science, medicinal chemistry, and pharmacology are designing, synthesizing, and biologically evaluating new multifunctional compounds to detect drugs for Trypanosoma and Leishmania infections.

Our research in the field of multitarget drugs may constitute a novel approach that could be applied to discovering new medicines for neglected tropical diseases. Although it is clear that many health issues in developing countries will not be solved by new technologies alone, novel medicines will still be important for reducing poverty and its consequences. Thus, political institutions should find the right way of uniting industry, investors, academic, and governmental organisations to intensify efforts toward the practical exploitation of new technologies against infectious tropical diseases.