Cysteine cathepsins as therapeutic targets in inflammatory diseases

Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract

“…They belong to lysosomal proteases involved mainly in intracellular protein breakdown, antigen processing, MHC-II mediated immune response, and apoptosis. However, their functions go far beyond this; they participate in various physio-pathological processes not only intracellularly, but also in the extracellular matrix (ECM), because, except for their endolysosomal sequestration, they have been observed in the nucleus, cytosol, mitochondria, at the plasma membranes and in the extracellular milieu[ 13 , 14 ]. Their secretion is observed in physiological conditions ( e.g.…”

“…Macrophages and other immune cells infiltrating tissues seem to be the main extracellular source of CCs whose secretion is stimulated by inflammatory factors like cytokines. However, also other cell types secrete excessive amounts of CCs, including osteoclasts or chondrocytes (oversecreting cathepsin K and/or S in arthritis and osteoporosis), or cancer cells and tumor-associated fibroblasts (oversecreting cathepsin S, L and/or B in cancer invasion)[ 14 ]. Apart from degradation of main components of ECM, also more refined processing of ECM (undergoing both intra-, and extracellularly) is ascribed to CCs.…”

“…Apart from degradation of main components of ECM, also more refined processing of ECM (undergoing both intra-, and extracellularly) is ascribed to CCs. This comprises modifying and shedding cell adhesion molecules and cell membrane receptors, which affects signal transduction pathways, as well as processing cytokines and chemokines, which upregulates immune response[ 14 ]. The resulting augmentation of inflammatory processes further induces the secretion of CCs, enhancing the destruction of ECM, which eventually leads to the acceleration of the processes observed in the aforementioned disorders.…”

“…However, the attempts to construct CCs-aimed drugs, taking advantage of the newest technology, are underway. The most clinical trials have been conducted on cathepsins K and S inhibitors, also cathepsin C seems to be a promising target, whereas the remaining cathepsins inhibitors have either got stuck in the initial stages of clinical trials or their trials have been discontinued (reviewed in[ 14 ]).…”

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“…Cathepsin S inhibitors also acts as immunomodulator 45 . Subsequently, there is a need to progress research efforts focused on cathepsin S use in diagnostics and as therapeutic targets in diseases 46,47 . Dipeptidyl nitrile inhibitor of cathepsin S has proved emerging target for abrogation of tumour 25 .…”