Trafficked Proteins—Druggable in Plasmodium falciparum?

Malaria is an infectious disease that results in serious health problems in the countries in which it is endemic. Annually this parasitic disease leads to more than half a million deaths; most of these are children in Africa. An effective vaccine is not available, and the treatment of the disease is solely dependent on chemotherapy. However, drug resistance is spreading, and the identification of new drug targets as well as the development of new antimalarials is urgently required. Attention has been drawn to a variety of essential plasmodial proteins, which are targeted to intra- or extracellular destinations, such as the digestive vacuole, the apicoplast, or into the host cell. Interfering with the action or the transport of these proteins will impede proliferation of the parasite. In this mini review, we will shed light on the present discovery of chemotherapeutics and potential drug targets involved in protein trafficking processes in the malaria parasite. 1. Introduction Malaria is a disease of global importance resulting in morbidity and mortality worldwide [1, 2]. Although, since 2000 a reduction in the mortality rate of about 25% has been globally observed, nearly half of the world’s population is still living at risk of infection [1, 3] leading to more than 0.5 million deaths annually [4]. Five species of the genus Plasmodium are known to infect humans; however, the most severe form of malaria, Malaria tropica, is caused by Plasmodium falciparum [5, 6]. Due to the spreading drug resistance against the currently used chemotherapeutics as well as environmental changes, the treatment of the disease is becoming more difficult. Resistance to therapeutics such as chloroquine and sulfadoxine-pyrimethamine is already widely distributed [28–31]. Furthermore resistance to Malarone, a combination of atovaquone and proguanil, became also apparent [32]. Currently only ACTs (artemisin-based combination therapies) are highly effective against malaria [33]. However, resistances to artemisinin and its derivatives have already been confirmed at the border of Cambodia-Thailand [34–36], and therefore the discovery of novel therapeutic agents against malaria is urgently required. Proliferation of P. falciparum within the asexual blood stage depends on haemoglobin digestion in the food vacuole [37]. This degradation pathway was already taken into consideration as a new drug target by focussing on the proteases plasmepsin I–IV [25]. However, since haemoglobin catabolism occurs in the food vacuole, not only inhibition of the catalytic properties of the digestive