Schistosomiasis Mansoni: Novel Chemotherapy Using a Cysteine Protease Inhibitor

Abstract

BackgroundSchistosomiasis is a chronic, debilitating parasitic disease infecting more than 200 million people and is second only to malaria in terms of public health importance. Due to the lack of a vaccine, patient therapy is heavily reliant on chemotherapy with praziquantel as the World Health Organization–recommended drug, but concerns over drug resistance encourage the search for new drug leads.Methods and FindingsThe efficacy of the vinyl sulfone cysteine protease inhibitor K11777 was tested in the murine model of schistosomiasis mansoni. Disease parameters measured were worm and egg burdens, and organ pathology including hepato- and splenomegaly, presence of parasite egg–induced granulomas in the liver, and levels of circulating alanine aminotransferase activity as a marker of hepatocellular function. K11777 (25 mg/kg twice daily [BID]), administered intraperitoneally at the time of parasite migration through the skin and lungs (days 1–14 postinfection [p.i.]), resulted in parasitologic cure (elimination of parasite eggs) in five of seven cases and a resolution of other disease parameters. K11777 (50 mg/kg BID), administered at the commencement of egg-laying by mature parasites (days 30–37 p.i.), reduced worm and egg burdens, and ameliorated organ pathology. Using protease class-specific substrates and active-site labeling, one molecular target of K11777 was identified as the gut-associated cathepsin B1 cysteine protease, although other cysteine protease targets are not excluded. In rodents, dogs, and primates, K11777 is nonmutagenic with satisfactory safety and pharmacokinetic profiles.ConclusionsThe significant reduction in parasite burden and pathology by this vinyl sulfone cysteine protease inhibitor validates schistosome cysteine proteases as drug targets and offers the potential of a new direction for chemotherapy of human schistosomiasis.

RNA interference of Schistosoma mansoni cathepsin D, the apical enzyme of the hemoglobin proteolysis cascade

“…The aspartic protease of HIV-1 is the target of several therapeutic drugs including saquinavir, ritonavir and lopinavir and moreover these HIV protease inhibitors also show anti-malarial activity probably by targeting one of more of the plasmepsin aspartic proteases of Plasmodium falciparum (see [35]). In addition, the papain-like cysteine proteases of S. mansoni which like schistosome cathepsin D also participate in hemoglobin proteolysis are being developed for new chemotherapeutic interventions including the vinyl sulfone cysteine protease inhibitor K11777 [36]. Indeed, lopinavir blocks schistosome cathepsin D activity against hemoglobin within the schistosome gut [6], which represents a potentially valuable lead for novel anti-schistosomal drug design.…”

Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs

“…Finally, other schistosome-specific enzymes, such as cysteine proteases (Abdulla et al 2007), may also be good targets for development of novel drugs.…”

The Use of Brazilian Medicinal Plants to Combat Schistosoma mansoni

“…activity (Rollas & Kuçukguzel, 2007). The most recent researches on new compounds or drugs with schistosomicidal activity have been carried out with: a) inhibitors of cysteine protease, such as K11777, considered a powerful schistosomicide that reduces the pathogenesis of experimental schistosomiasis (Abdulla et al, 2007), b) RNAi, in the attempt to develop drugs or compounds that act as enzyme silencers, e.g., the compound 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide, or furoxan, which acts on thioredoxin-glutathione reductase from S. mansoni (Kuntz et al, 2007, Sayed et al, 2008, c) trioxolanes or secondary ozonides (1, 2, 4-trioxolanes), which comprehend a class of synthetic endoperoxides that are cheap, easily synthesised, and similar to artemisinins, having activity on experimental infections with S. mansoni and S. japonicum (Caffrey, 2007, Xiao et al, 2007, d) mefloquine (antimalarial), which showed schistosomicidal activity against young and adult S. mansoni worms (Van Nassauw et al, 2008, Keiser et al, 2009), e) arachidonic acid, which showed schistosomicidal properties against S. mansoni and S. haematobium ( E l R i d i e t a l . , 2010), and f) miltefosine (antileishmania), which reduced the parasite burden of mice infected with S. mansoni (Eissa et al, 2011).…”