The Inhibition of Cysteine Proteases Rhodesain and TbCatB: A Valuable Approach to Treat Human African Trypanosomiasis

Abstract

Human African Trypanosomiasis (HAT) is an endemic parasitic disease of sub-Saharan Africa, caused by two subspecies of protozoa belonging to Trypanosoma genus: T. brucei gambiense and T. brucei rhodesiense. In this context the inhibition of the papain-family cysteine proteases rhodesain and TbCatB has to be considered a promising strategy for HAT treatment. Rhodesain, the major cathepsin L-like cysteine protease of T. brucei rhodesiense, is a lysosomal protease essential for parasite survival. It is involved in parasite invasivity, allowing it to cross the blood-brain barrier (BBB) of the human host, causing the second lethal stage of the disease. Moreover, it plays an important role in immunoevasion, being involved in the turnover of variant surface glycoproteins of the T. brucei coat and in the degradation of immunoglobulins, avoiding a specific immune response by the host cells. On the other hand TbCatB, a cathepsin B-like cysteine protease, present in minor abundance in T. brucei, showed a key role in the degradation of host transferrin, which is necessary for iron acquisition by the parasite. In this review article we now discuss the most active peptide, peptidomimetic and non-peptide rhodesain and TbCatB inhibitors as valuable strategy to treat HAT, due also to the complementary role of the two T. brucei proteases.

New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain

“…The cathepsin L-like protease rhodesain from Trypanosoma brucei rhodesiense, the parasite causing human African trypanosomiasis (HAT), is essential for the parasite's survival, since it is involved in several pathological processes in the host. These include, e.g., the crossing of the parasite through the blood-brain barrier as well as the turnover of variant surface glycoproteins (VSGs), and degradation of host immunoglobulins [40,41].…”

Development of Novel Benzodiazepine‐Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense

“…In the present scenario, there is an urgent need to identify new targets for the development of novel drugs for HAT treatment. In this context rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense is currently considered an interesting target for the new drug discovery process, due to its key functions . First, rhodesain has a key role in lysosomes for the proteolysis of both protozoan and host proteins transported within the parasite, it is involved in escaping the immune system with two main mechanism: by degrading the host immunoglobulins and with the turnover of the variant surface glycoprotein (VSGs) of Trypanosoma coat.…”

“…First, rhodesain has a key role in lysosomes for the proteolysis of both protozoan and host proteins transported within the parasite, it is involved in escaping the immune system with two main mechanism: by degrading the host immunoglobulins and with the turnover of the variant surface glycoprotein (VSGs) of Trypanosoma coat. Lastly, the trypanosomal protease is also responsible for the onset of the neurological stage of the disease due to its capability to degrade BBB components …”

“…In the designed compounds, we maintained the benzodiazepine (BDZ) scaffold as a β‐turn mimetic, which is often suggested as the structural motif of the active form of linear peptides; in addition, this nucleus has optimal oral bioavailability and tolerability, as widely demonstrated by the large use of BDZs as drugs. Instead of the aliphatic spacer between BDZ nucleus and the warhead, we introduced some structural elements of utmost relevance for the inhibition of rhodesain, that is, the P2‐P1 Phe‐hPhe sequence, often present in the backbone of several potent rhodesain inhibitors . On these basis, in the structure of compounds 2 a – g the hPhe residue is present at position P1, whereas the P2 Phe is mimed by the condensed phenyl ring of the BDZ nucleus.…”

Genes codificadores de proteínas implicadas na relação de espécies do gênero <i>Trypanosoma</i> com seus hospedeiros: diversidade, transferência horizontal e relações filogenéticas.

“…Estudos sugerem que todas as cisteína proteases similares com Catepsina L são homologas e divergiram, originando diversas variantes ao longo do processo de especiação (Sajid, McKerrow, 2002). Os genes de Catepsina L de tripanossomas têm sido usados com sucesso para diagnóstico, genotipagem, alvos terapêuticos e estudos evolutivos em T. theileri, T. rangeli, T. cruzi, T. brucei e T. vivax (Cortez et al 2009;Ettari et al 2016;Garcia et al 2011aGarcia et al , 2011bJefferson et al 2016;Lima et al 2012a;Nakayima et al 2013;Rodrigues et al 2010Rodrigues et al , 2015Ortiz et al 2009). A grande diversidade de funções exibidas por essas proteases pode ter contribuído para complexidade do ciclo de vida e o grande número de hospedeiros e vetores observados em Trypanosoma (Alvarez et al, 2012;Atkinson et al, 2009;Lima et al, 2012a).…”