Host and Pathogen-Specific Drug Targets in COVID-19
Debmalya Barh, Kenneth Lundstrom in COVID-19, 2022
Cathepsins are proteases that function to recycle/degrade cellular proteins. There are 11 types of cathepsins that are usually found within the endosomes/lysosomes (see Figure 10.2). They exist mainly as precursor enzymes, which require acidic pH for activation. Cathepsin L, a serine protease seems to be highly associated with the SARS-CoV-2 S protein. Once inside endosomes, cathepsin L further cleaves the SARS-Cov-2 S protein. This allows the membrane fusion of the viral envelope and endosomes, a critical step for the release of the viral genome into the cytoplasm [75]. The anti-Ebola cysteine protease inhibitor K11777, which specifically targets cathepsin, has been shown also to have some positive effects on SARS-CoV-2 [77]. As mentioned earlier, the Mpro inhibitor GC-376, also seems to exert cross reactivity with Cathepsin-L [45]. Furthermore, some evidence suggests that cathepsins work in cohort with TMPRSS2 to fully achieve effectiveness for SARS-CoV-2 entry [75]. This implies that combining drugs such as camostat with K11777 may optimize the therapy.
Inflammation
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
Lysosomal enzymes are associated with intracellular digestive functions in phagocytic cells. Neutrophil leukocytes and macrophage granules are the major sources of lysosomal enzymes in the inflammatory response. The lysosomal enzymes degrade all types of macromolecules, such as proteins, peptides, carbohydrates, nucleic acids and lipids. Some of these enzymes are presented in Table 5, showing the similarity with enzymes occurring in neutrophil granules (Table 4). All cathepsins have broad substrate specificity and occur in multiple forms with identical catalytic activity.22 Elastase and cathepsin G stimulate lymphocytes and initiate antibody production.475 Neutral lysosomal proteases cleave C and C5 fragments into active chemotactic agents488 and activate kininogen to bradykinin and plasminogen to plasmin.193 Neutrophil leukocytes contain collagenases which split GLY-ILE or GLY-LEU bonds in collagen, yielding smaller peptide fragments which are further degraded by elastase, cathepsin B, or metalloproteinase enzymes.30,268,324
Pathology of the Liver: Functional and Structural Alterations of Hepatocyte Organelles Induced by Cell Injury
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
The lysosomal cathepsins play a major role in degradation of cellular proteins. These proteinases have acid optima (pH 3–5) and they become inactive and unstable at neutral or alkaline pH. In addition, cytosolic inhibitors bind and inactivate cathepsins that may leak out of the lysosomes of injured cells. The lysosome is the major intracellular site for the degradation of lipids as can be inferred by the accumulation of lipids that occurs in lysosomal enzyme-deficiency states (Glew et al., 1985). Phospholipid turnover in the liver is rapid. The estimates of half-lives for phospholipids range from approximately 10 h to 2 days depending on the labelled precursor used to measure the turnover (Van Den Bosch, 1980). Phospholipases are also found in the cytosol and in all the various cellular membranes where they act in concert with lysophospholipid acyltransferases to remodel phospholipids (Van Den Bosch, 1980).
Macrophages in the reticuloendothelial system inhibit early induction stages of mouse apolipoprotein A-II amyloidosis
Published in Amyloid, 2023
Hiroki Miyahara, Jian Dai, Ying Li, Xiaoran Cui, Hibiki Takeuchi, Naomi Hachiya, Fuyuki Kametani, Masahide Yazaki, Masayuki Mori, Keiichi Higuchi
Based on our in vitro results, the proteolytic cleavage of AApoAII fibrils in lysosomes is one of the key processes for degradation. The inhibition of cathepsin B activity was critical for impairing the phagocytic degradation of internalized amyloid fibrils (Figure 3(I)). It is reported that autolysosomes are impaired in neurons before extracellular amyloid deposition in AD model mice [43]. Decreased levels of lysosome-associated proteins and impaired activity are observed in various cells of aged mice [44–46]. Moreover, young microglia-derived inflammatory factors enhance the proliferation and lysosomal activity of microglia, resulting in enhanced amyloid clearance properties [45]. Hence, there might be pathological mechanisms regarding the association between endosomal-lysosomal integrity and initiation of spontaneous AApoAII progression.
Beyond basic research: the contribution of cathepsin B to cancer development, diagnosis and therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Andrey A Zamyatnin, Levy C Gregory, Paul A Townsend, Surinder M Soond
Over the last 3 years, the cathepsin proteases and their clinical applications have made great gains in the field of cancer research. Whilst they were originally thought of as proteases that had an important function in cellular homeostasis, their biological effects have been furthered as important players in a number of key regulatory mechanisms that span cell proliferation, survival, differentiation, and ECM regulation. As a versatile member of this family of proteases, clearly cathepsin B has been seen to have gathered heightened importance based on the wealth of knowledge that has been gained from its utilization as a diagnostic and prognostic marker for a number of cancers, and from it being therapeutically targeted and tested in preliminary clinical trials. When taken together, CtsB is clearly a protein that is shaping the paradigms through which we view this family of proteases from a basic-research perspective and with the forethought of how such findings may translate with tangible effects in the clinical.
A patent review on cathepsin K inhibitors to treat osteoporosis (2011 – 2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Fernanda R. Rocho, Vinícius Bonatto, Rafael F. Lameiro, Jerônimo Lameira, Andrei Leitão, Carlos A. Montanari
Cathepsin K is a papain-like cysteine protease highly expressed in osteoclasts and is considered a biological target for bone-related diseases, such as osteoporosis. Thus, new chemical entities have been developed in the last decade as potential new treatments for osteoporosis via inhibition of CatK. This review summarizes findings in the patent literature filed between 2011–2021, showing the most promising compounds. In this period, new classes of warheads were introduced, and derivatives of the clinical candidates Odanacatib and Balicatib are still being exploited. Encouraging results were achieved with the design of highly potent and selective CatK inhibitors coupled to in vitro and in vivo improved properties. Furthermore, a new activity-based probe that acts as a substrate of CatK was filed. The probe could track down abnormal bone resorption by targeting CatK activity and might be a valuable tool for future research.