Cruzain and Rhodesain Inhibitors: Last Decade of Advances in Seeking for New Compounds Against American and African Trypanosomiases

Abstract

: Neglected tropical diseases (NTDs) are a group of approximately 20 diseases that affect part of the population in Sub- and Tropical countries. In the past, pharmaceutical industries and governmental agencies have invested in the control, elimination and eradication of such diseases. Among these diseases, Chagas disease (CD) and Human African trypanosomiasis (HAT) are a public health problem, mainly in the countries from the American continent and sub-Saharan African. In this context, the search for new therapeutic alternatives against such diseases has been growing in recent years, presenting cysteine proteases as the main strategy to discover new anti-trypanosomal drugs. Thus, cruzain and rhodesain enzymes are targets widely studied, since the cruzain is present in all stages of the parasite's life, related to the stages of proliferation and differentiation and infection of macrophages; while the rhodesain is related to the immune defense process. In addition, knowledge about the amino acid sequences and availability of X-ray complexes have stimulated the drug searching against these targets, mainly through molecular modeling studies. Thus, this review manuscript will be addressed to cruzain and rhodesain inhibitors developed in the last 10 years, and which could provide basis for new lead compounds in the discovery of new trypanocidal drugs. We found 117 studies involving inhibitors of cruzain and rhodesain, being thiosemicarbazones, semicarbazones, N-acylhydrazones, thiazoles-hydrazone, thiazolidinones-hydrazones, oxadiazoles, triazoles, triazines, imidazoles, peptidomimetic, and others. All references were obtained using “cruzain” or “rhodesain” and “inhibitor” as keywords in Science Direct, Bentham Science, PubMed, Espacenet, Springer, ACS Publisher, Wiley, Taylor and Francis, and MDPI (Multidisciplinary Digital Publishing Institute) databases. Finally, we highlighted all these chemical classes of molecules to provide valuable information that could be used to design new inhibitors against Chagas disease and sleeping sickness in the future.

Virtual screening based on covalent docking and MM-PBSA calculations predict the drugs neratinib, sacubitril, alprostadil, trandolapril, and florbetapir as promising cruzain inhibitors useful against Chagas disease.

“…The ligands showed a fit score between 49.85 -94.18 (Table 1), and a covalent fit score varying between 49.91 -141.52 (Table 1). In addition, it was observed that the compounds with conventional fit score and covalent fit score better than 55 and 90, respectively, showed interactions with the main residues related to the cruzain inhibition (Cys 25 , His 159 , Glu 23 , Gly 65 , and Glu 205 ) [3,5,6,26,27] (Table 1). Other works used a similar protocol to search new hits to drug design [10,28,29].…”

“…With PDB crystal structure, GOLD ® algorithm selected and the start point values for screening the drugs, the next stage was built the ligand dataset. For this, 1615 FDA-approved drugs from the ZINC database were visually analyzed for choosing the drugs with chemical groups that can interact covalently with the sulfur atom of Cys 25 from cruzain [3]. This analysis resulted in the selection of 241 drugs that contained ester, carbon α-halogenated, nitrile, amide, and alkenes, and alkyne.…”

“…Among these, Chagas disease has been causing concern in health agencies worldwide due to the growing number of cases in recent years, endemic in more than 21 countries, with estimates of approximately 6 to 7 million infected, and 75 million in risk situation [1]. Despite presenting alarming data, there are only two drugs approved for the treatment (nifurtimox and benznidazole), being a challenge for medicinal chemists worldwide to discover a new innovative treatment [3].…”

“…Among the most explored targets in drug design in the search for new drugs against Chagas disease is cruzain [3]. This enzyme is key in several biochemical processes of the parasite, such as invasion, differentiation, proliferation, and degradation of host cell proteins, contributing to the infectious process [4].…”

Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors

“…cruzi . Moreover, it is recognized by the host as an antigen and modulates the host macrophage response. , Tbr CATL is important for penetration through the blood–brain barrier and is essential for parasite survival. ,, Efforts to develop inhibitors have led to the discovery of many potent chemotypes against both proteases (reviewed in refs , , and ). Recently reported inhibitors include peptidomimetics − and nonpeptidic small molecules that inhibit the enzymes irreversibly or reversibly. − In addition to their efficacy in in vitro assays against trypanosomes, ,,, cysteine protease inhibitors have shown efficacy in mice − and dog models of Chagas disease, and to reduce parasitemia and/or increase survival ,, in mouse models of T.…”