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  • GSK1904529A receptor br Introduction Schistosomiasis one of

    2019-10-31


    Introduction Schistosomiasis, one of the major parasitic diseases that affect humans in tropical and subtropical countries, is an acute and chronic condition caused by blood flukes (trematode worms) of the genus Schistosoma (World Health Organization, 2014). Schistosomiasis infects over 240 million people worldwide, and more than 700 million are at risk in endemic areas (World Health Organization, 2018). Patients with schistosomiasis are highly susceptible to malaria, tuberculosis, hepatitis and acquired immunodeficiency viruses (El Ridi et al., 2015). Therefore, it is important to improve the control of schistosomiasis and urgent efforts should be made towards the development of new antischistosomal drugs and vaccines. The chemotherapy currently available against schistosomiasis relies on the administration of Praziquantel (PZQ) (Cioli and Pica-Mattoccia, 2003), because it is orally effective against all five species of schistosomes with a single-day treatment. It is efficient against adult worms, but does not kill larvae or prevent reinfection (Thétiot-Laurent et al., 2013). Preventive vaccination would clearly overcome re-infection problems, avoiding the need for repeated treatments of people living in endemic areas. Although PZQ resistance and sporadic cases of decreased drug sensitivity have been reported, these facts are not enough to undermine the public health value of PZQ (Cioli et al., 2014). The mechanism of action of praziquantel is still unclear, a fact that does not favor the development of derivatives or alternatives. In Schistosoma, a series of GSK1904529A receptor have been identified and validated as potential chemotherapeutic targets (Ferreira et al., 2015) and as promising vaccine candidates. Cysteine proteases are involved in important physiological processes, including digestion, immunity, antimicrobial function, (immune) signaling, apoptosis and as transcriptor factors (Dall and Brandstetter, 2016). They are fundamental to the establishment and pathogenesis of many parasitic infections (Sajid and McKerrow, 2002) and have been organized into evolutionary families and clans (Barrett and Rawlings, 2001). Within this group, the clan CD contains important members such as legumains (EC 3.4.22.34) which were originally identified in leguminous plants and in the parasitic blood fluke S. mansoni (Sajid and McKerrow, 2002). The CD13 cysteine protease of S. mansoni (Sm32, also known as SmAE or schistosome legumain) is an asparaginyl endopeptidase (AE) that cleaves C-terminal to asparaginyl (Asn) residues (Dalton et al., 2009). This protein has been characterized, cloned and sequenced (Klinkert et al., 1989; Davis et al., 1987; Caffrey et al., 2000) and is detected in the gut gastrodermis and in the parasite caecal-lumen (Sajid and McKerrow, 2002). Host haemoglobin, together with other plasma proteins, is the most important source of nutrients (amino acids and iron) for the parasitic blood fluke S. mansoni (Chappell and Dresden, 1986). Sm32 was considered to be responsible for the degradation of host haemoglobin within the parasite gut (Götz and Klinkert, 1993). However, it has been proposed that rather than directly digesting blood proteins in the gut, the enzyme is involved in the proteolytic activation of other endopeptidases that perform this function (e.g. Cathepsin B1). In schistosomes, one of the roles of Sm32 might be to process native cathepsin B1 (Sm31or SmCB1) to its mature form, which is a papain-like cysteine proteinase. Nevertheless, Krautz-Peterson and Skelly (Krautz-Peterson and Skelly, 2008) showed that a substantial suppression in Sm32 protein levels has no effect on Sm31 processing or activity and therefore it is not essential for Sm31 activation in vivo. It has been proposed that the primary role of the enzyme was the trans-processing and activation of other schistosome proteases after noting that zymogens of clan AA aspartic proteases (cathepsin D) and clan CA cysteine proteases (cathepsins L, F, B1 and C) each possessed an AE-cleavage site at the juncture between the prosegment and the mature enzyme domain. Prosegment removal by trans-processing exposes the active site of the mature enzyme to enable the entry of haemoglobin substrate (Dalton et al., 2009).