br Conclusions Present work comprehensively
Conclusions Present work comprehensively characterizes the inhibitory activity of Yersinia enterocolitica against cysteine proteases. All tested strains, regardless of their bioserotype, genotype and the presence of virulence markers, synthesized the high-molecular-weight inhibitors of papain and human cathepsin L, but not cathepsin B. One such proteinaceous inhibitor was identified as the periplasmic chaperone Skp, possibly related to the survival of the bacteria within their host. The homologous Skp protein was also isolated from the extract of Escherichia coli. Skp-containing eluates inhibited the activity of cysteine cathepsins produced by human dermal fibroblasts, what shows this chaperone as a potential drug for the treatment of cysteine cathepsin-driven diseases.
Conflict of interest
Acknowledgements This work was supported in part by the project „Academy of Development as the key to strengthen human resources of the Polish economy”, co-financed by the European Union under the European Social Fund, as well as by the Ministry of Science and Higher Education (Poland) within the statutory research [project no. 0420/1402/16]. The equipment used for protein identification by peptide mass fingerprinting was sponsored in part by the Centre for Preclinical Research and Technology (CePT), a project co-sponsored by European Regional Development Fund and Innovative Economy, The National Cohesion Strategy of Poland.
Introduction Cysteine proteases are members of the papain-like peptidase family (Turk et al., 2012). Having unique active site properties, these enzymes are expressed during the entire life BYL719 of trypanosomatid parasites and are essential to different cellular processes, such as nutrition, reproduction, invasion of host cells, and circumvention of the host immune system (Sajid & McKerrow, 2002). These different roles of cysteine proteases are pivotal to the onset and progression of diseases caused by these pathogens. As a result of the better understanding of the role of these enzymes in disease physiopathology, inhibition of cysteine proteases by small-molecule compounds has proved to be a practical strategy in drug discovery for parasitic infections. To that end, considerable efforts have been made to demonstrate the essentiality of cysteine proteases for parasite survival. As a result, these enzymes have been validated as molecular targets for neglected tropical diseases (NTDs), such as Chagas disease and human African trypanosomiasis (HAT) (Steverding et al., 2012). In this context, cruzain from Trypanosoma cruzi and rhodesain and cathepsin B (TbCatB) from Trypanosoma brucei have been explored in drug discovery efforts (Kerr et al., 2010, Martinez-Mayorga et al., 2015). As forefront drug discovery technologies have recently been adopted in the field of NTDs, current efforts targeting these proteases have made valuable progress toward novel drug candidates. An additional noteworthy aspect in this area is the engagement of public-private partnerships (PPPs) that have taken the responsibility to lead global cooperative programs dedicated to drug discovery for tropical diseases.
Neglected tropical diseases The term NTD was coined by WHO to designate 18 conditions predominantly caused by parasites that mainly occur in developing countries. Altogether, these diseases affect approximately one billion people, particularly in Latin America, Asia and Africa (Molyneux, Savioli, & Engels, 2017). In addition to the predominance of NTDs in these regions, wealthy nations have become affected due to increased population migration (Alirol, Getaz, Stoll, Chappuis, & Loutan, 2011), which has contributed to an increase in international awareness regarding these diseases, resulting in the growth of research efforts, mainly by the establishment of PPPs. These global cooperative networks have supported a consistent increase in drug research and development (R&D) funding, especially over the past 10years. Including pharmaceutical companies, not-for-profit organizations and academic and research institutions, these initiatives have catalyzed the transference of up-to-date technologies to the field, and they are currently the forefront organizational model in NTD drug discovery (Jakobsen, Wang, & Nwaka, 2011). Despite the advances promoted by these valuable efforts, the few pharmacological agents available for the treatment of these diseases have serious efficacy and safety drawbacks. In this context, the discovery of new, effective, and safe drugs is critical for these highly prevalent and life-threatening conditions.