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Spontaneous Intestinal Perforation (SIP) is not Necrotizing Enterocolitis (NEC) But Remains the Major Confounder of NEC Data
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Phillip V. Gordon, Jonathan R. Swanson, Reese H. Clark
The ontogeny of SIP is not inflammatory; rather, it is likely a consequence of aberrant trophism. During the perinatal period, the gut mucosa is exquisitely sensitive to steroids. In fact, research into SIP yielded the discovery of several new mechanisms by which steroids interface with growth factors affecting the mucosa and the mesenchyme (67–70). Central to this is a protease known as cathepsin L, which has been shown to have increased expression and intestinal epithelial cell membrane binding with steroids. It is an enzyme that alters the bioavailability of IGF via catabolism of IGF-binding proteins (IGFBPs). IGF-I has been demonstrated to be the principal growth factor responsible for submucosal thickness, and bowel wall tensile strength has long been known to be derived from the submucosa (Figure 7.4). Steroids strip IGF-I from the submucosa, thinning it rapidly and thereby increasing the risk of perforation over a period of days.
Major Histocompatibility Complex and Autoimmune Disease
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Ursula Holzer, Gerald T. Nepom
The two main proteases involved in the degradation of the Ii chain are cathepsin L and S, which are differently distributed in tissues. Whereas cathepsin L is expressed in cortical thymic epithelial cells (cTEC), which present endogenous peptides to maturing thymocytes, cathepsin S is found in bone marrow-derived APCs like dendritic cells, macrophages or B-cells.20 Interestingly, cathepsin S deficient mice exhibit significantly diminished susceptibility to collagen-induced arthritis, the mouse model for human rheumatoid arthritis,21 thus suggesting that the proteolytic pathway involving antigen and the Ii chain are involved in processing and recognition of target antigens in this model of induced autoimmunity.
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Two cysteine proteases structurally related to human cathepsin L, cruzain of T. cruzi and rhodesain of T. brucei rhodesiense, have been subject to drug development efforts, including many computational and mechanistic studies in the past years, which we review below. More details on inhibitor design against cysteine proteases in Trypanosoma can be found in the recent review by Ferreira and Andricopulo (2017).
Drug repurposing strategies and key challenges for COVID-19 management
Published in Journal of Drug Targeting, 2022
Shubham Mule, Ajit Singh, Khaled Greish, Amirhossein Sahebkar, Prashant Kesharwani, Rahul Shukla
Proteases-mediated cleavage of the spike protein of virus is a preliminary requirement in viral infection. Various lysosomal cathepsins play their role in the endocytosis-mediated entry of virus in host cell [29]. In an investigation conducted recently, it was observed that only the cathepsin L is responsible in the cellular entry of the SARS-COV2 [58]. SSAA09E is an inhibitor of cathepsin L emerged as a novel antiviral drug [59]. When SID26681509, a selective inhibitor of cathepsin L, was used to treat HEK 293/hACE cells, the cellular entry of the virus was found to be dampened by around 76% [60]. Cathepsin L inhibitors have the extra advantage of preventing the emergence of pulmonary fibrosis in COVID patients [61]. Targeting actively cathepsin L and TMPRSS2 simultaneously may also provide synergistic activity [62]. However, the main obstacle in the development of cathepsin inhibitors is to achieve selectivity for cathepsin L.
COVID-19 during Pregnancy and Postpartum:
Published in Journal of Dietary Supplements, 2022
Sreus A. G. Naidu, Roger A. Clemens, Peter Pressman, Mehreen Zaigham, Kelvin J. A. Davies, A. Satyanarayan Naidu
LF effects on viral cell entry: Proteolytic degradation of proteins from both the host and the virus is critical for several physiological processes. Neutrophils secrete LF and serine proteases such as cathepsin G (CatG), neutrophil elastase (NE), and proteinase 3 (PR3) in response to microbial challenge. LF increases the catalytic activity and broadens the substrate selectivity of CatG during inflammatory conditions (acidic pH 5.0). LF also enhances CatG-induced expression of cell surface expression of CD62P and activates platelets. Consequently, LF-mediated enhancement of CatG activity might promote innate immunity during acute inflammation (Eipper et al. 2016). Milk LF and β-casein are potential inhibitors of cysteine proteases. LF is a strong inhibitor of cathepsin L activity. The inhibition kinetics of LF are noncompetitive and heat-sensitive, which suggests that the tertiary structure of LF is critical for the activity (Ohashi et al. 2003).
SARS-CoV-2 protein drug targets landscape: a potential pharmacological insight view for the new drug development
Published in Expert Review of Clinical Pharmacology, 2021
Chiranjib Chakraborty, Manojit Bhattacharya, Bidyut Mallick, Ashish Ranjan Sharma, Sang-Soo Lee, Govindasamy Agoramoorthy
The spike glycoprotein of this virus is cleaved by the proteases such as cathepsin L. The S1 site/S2 site of S glycoprotein can be cleaved cathepsin L [106]. The S1 site/S2 site cleavage a key step in viral infection and the proteases cathepsins may help in human coronavirus entry through endocytosis [107]. Different bioinformatics tools are being applied to understand the cathepsin L cleavage sites in proposed protein substrates and the structure has been determined (PDB ID: 6JD0). But, it’s yet to be published as per the protein data bank. Other crystal structures of cathepsin L are available (PDB code: 4AXL) [108] and there are several active cites of cathepsin L that can act as drug binding sites (Figure 3A). Fujishima et al. has demonstrated that the structural differences between cathepsin L and cathepsin B, where the S’ subsites of the both two enzymes to be totally different. They have also found that The S2 pocket of cathepsin L to be superficial and different from cathepsin B [109] and it will help to design the specific and effective inhibitors. However, the cathepsin L inhibitors may serve as a therapeutic choice for SARS-CoV-2 and drug design using this enzyme may prevent the progression of pulmonary fibrosis [110]. Cathepsin L inhibitors such as E64d or MDL28170 have been shown to inhibit SARS-CoV-2 replication. Moreover, dual inhibitors such as calpain inhibitors II and XIIthat target both cathepsin L and viral main protease have been reported to inhibit SARS-CoV-2 replication in cell culture, and the structures of calpain inhibitors II and XII in complex with Mpro have been solved [111,112].