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Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
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.
Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Elafin, isolated from horny layers of human skin, comprises 57 residues with 38% identity to the second domain of ALP.72 The inhibitor is effective against human neutrophil elastase, pig pancreatic elastase,72 and human neutrophil proteinase 3,73 but shows no activity against cathepsin G, chymotrypsin, or trypsin (Ki calculated to be above 10−7M from published data73). Its function is unknown, although its location and selectivity would suggest a role in protecting skin layers from neutrophil elastolytic enzymes.
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
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
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.
Porphyromonas gingivalis infection may contribute to systemic and intracerebral amyloid-beta: implications for Alzheimer’s disease onset
Published in Expert Review of Anti-infective Therapy, 2020
Another focus of Nie and colleagues [32] was Aβ1-42, which is classically considered as the toxic form of Aβ. They observed that Aβ3-42 (Figure 1) not only occurred earlier but was also two-fold higher than Aβ1-42 in the AD brain[32]. In AD, cathepsin B stimulated intracellular production of Aβ in the brain, including the Aβ3-42. Interestingly, Aβ3-42 following P.gingivalis-infection in mice generated IL-1β, which is a proinflammatory cytokine[32]. IL-1β participated in increasing the in vivo levels of Aβ3-42 in the hepatic macrophages of P.gingivalis-infected mice and in vitro P.gingivalis-infected macrophages. Furthermore, Aβ3-42 was induced by P.gingivalis infection, which had caused significant death of macrophages and reduced their phagocytic capacity compared to that of Aβ1-42, suggesting Aβ3-42 is very toxic. Aβ3-42 was also detected exclusively in the AD brain, and this corroborates with the significantly more toxic form than Aβ1-42[32]. This study agreed with that of Leira et al. [34] who reported that LPS from P.gingivalis increased Aβ protofibrils in the serum of rats. After experimental periodontitis had been induced in male Sprague-Dawley rats, it caused an acute elevation of Aβ1-40 in serum that lasted during the whole experiment. Aβ1-42 peptide levels, however, peaked at the end of the study.