Development of Plasmodium falciparum protease inhibitors in the past decade (2002-2012).

New drug targets for the development of antimalarial drugs have emerged after the unveiling of the Plasmodium falciparum genome in 2002. Potential antimalarial drug targets can be broadly classified into three categories according to their function in the parasite's life cycle: (i) biosynthesis, (ii) membrane transport and signaling, and (iii) hemoglobin catabolism. The latter plays a key role, as inhibition of hemoglobin degradation impairs maturation of bloodstage malaria parasites, ultimately leading to remission or even cure of the most severe stage of the infection. Intraerythrocytic Plasmodia parasites have limited capacity to biosynthesize amino acids which are vital for their growth. Therefore, the parasites obtain those essential amino acids via degradation of host cell hemoglobin, making this a crucial process for parasite survival. Several plasmodial proteases are involved in hemoglobin catabolism, among which plasmepsins and falcipains are well-known examples. Hence, development of P. falciparum protease inhibitors is a promising approach to antimalarial chemotherapy, as highlighted by the present review which is focused on the Medicinal Chemistry research effort recorded in the past decade in this particular field.

Falcipains, Plasmodium falciparum cysteine proteases as key drug targets against malaria.

There is a high demand for new drugs against malaria, which takes millions of lives annually. The abuse of classical antimalarials from the late 1940's to the early 1980's has bred resistant parasites, which led to the use of more potent drugs that ended up by refueling the resistance cycle. An example is chloroquine, once highly effective but now virtually useless against malaria. Structure-based rational drug design relies on high-resolution target structures to allow for screening of selective ligands/inhibitors. For the past two decades, and especially after the unveiling of the Plasmodium falciparum genome in 2002, enzymes of this lethal malaria parasite species have been increasingly attracting the attention of Medicinal Chemists worldwide as promising drug targets. There is particular emphasis on proteases having key roles on the degradation of host's hemoglobin within the food vacuole of blood-stage parasites, as these depend on such process for their survival. Among such enzymes, Plasmepsins (aspartic proteases) and, especially, Falcipains (cysteine proteases) are highly promising antimalarial drug targets. The present review will focus on the computational approaches made so far towards the unraveling of the structure, function and inhibition of Falcipains that, by virtue of their quite specific features, are excellent targets for highly selective inhibitors.

Prognostic factors for death from visceral leishmaniasis in Teresina, Brazil.

BACKGROUND: A possible strategy to reduce fatality rates of visceral leishmaniasis is to identify prognostic factors that can be easily assessed and used as an aid to clinical decision-making. PATIENTS AND METHODS: A case-control study was developed in Teresina, Brazil, in which cases were patients who died during treatment (n = 12) and controls (n = 78) comprised a random sample of patients who were alive when treatment was finished. RESULTS: Variables significantly associated with death were severe anemia, fever for more than 60 days, diarrhea and jaundice. The prognostic system had a sensitivity of 85.7% and a specificity of 92.5%. CONCLUSION: The prognostic model developed in this study had satisfactory performance and might be useful in developing countries, since it is simple and inexpensive. However, it is still preliminary and needs to be improved and validated using larger and more recent samples.