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  • br Cysteine proteases as molecular targets for

    2021-01-18


    Cysteine proteases as molecular targets for trypanosomatid diseases Approaches relying on a molecular target, such as SBDD and target-based screening, have supported outstanding scientific developments in current pharmaceutical R&D. By integrating experimental and computational methods, these strategies have been used in the identification and optimization of ligands with notable potency and selectivity against their respective molecular targets (Ferreira, Dos Santos, Oliva, & Andricopulo, 2015). The prevalence of this approach within the industry has been compelled by the remarkable progress in the understanding of the molecular underpinnings of disease and has been sustained by advances in areas such as genomics and molecular, chemical and structural biology (Schenone, Dančík, Wagner, & Clemons, 2013). Supported by this biotechnological basis, target-based drug research depends strongly on validation studies, i.e., the demonstration that selective modulation of the molecular target results in the expected clinical outcome (Wyatt, Gilbert, Read, & Fairlamb, 2011). In this context, cysteine proteases have been investigated in drug discovery for Chagas disease and HAT. Molecular biology, immunology, pharmacology and medicinal chemistry studies have been conducted to reveal the functions of these phenylephrine hydrochloride and to validate them for drug discovery purposes (Steverding et al., 2012). Structural aspects and biological roles of the cysteine proteases cruzain, rhodesain and TbCatB, and studies demonstrating the relevance of these enzymes as pharmacological targets are examined next.
    Conclusions Cysteine proteases are validated drug targets for the development of safe and effective pharmacological agents for trypanosomatid diseases. Several genetic and chemical validation studies have confirmed the essentiality of these enzymes in the various stages of the T. cruzi and T. brucei life cycle. Moreover, there is an increasing volume of evidence demonstrating the diverse roles of cruzain, rhodesain and TbCatB in the parasite-host interplay and disease pathophysiology. Considering these findings, the deficiencies in the current chemotherapy and the scarcity of validated pharmacological targets, cysteine proteases will continue to be broadly explored in drug discovery for Chagas disease and HAT. Current target-based screenings have identified new chemotypes as promising hits, which have been subjected to SBDD and medicinal chemistry studies aimed at optimizing pharmacodynamics and pharmacokinetics. By employing these strategies, the research community dedicated to NTD drug discovery has generated fundamental and applied knowledge that has been pivotal to the development of the field. In this context, potent and selective compounds containing innovative chemical scaffolds have recently been reported. The development of the cruzain inhibitor K-777 is a representative case, as it created positive prospects for advancing to clinical development. Another promising chemical class, fluoroketones, has produced remarkably potent cysteine protease inhibitors, showing nanomolar-range activity and convenient pharmacokinetics in preclinical programs. Overall, these drug R&D programs in Chagas disease and HAT have been fostered by notable improvements in the scientific and technological framework in the past 10years. The implementation of partnerships between research institutions, not-for-profit organizations and the pharmaceutical industry has enabled the advancement of decisive multilateral efforts that catalyze several necessary areas of expertise, such as structural biology, organic synthesis, medicinal chemistry and pharmacology. Such a multidisciplinary approach, focused on the specific needs and goals of NTD drug discovery, is required to surmount the leading issues in the development of protease inhibitors, such as poor pharmacokinetics and selectivity over human peptidases.
    Conflict of interest statement
    Acknowledgment