Spontaneous Intestinal Perforation (SIP) is not Necrotizing Enterocolitis (NEC) But Remains the Major Confounder of NEC Data
David J. Hackam in Necrotizing Enterocolitis, 2021
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
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
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.
Host and Pathogen-Specific Drug Targets in COVID-19
Debmalya Barh, Kenneth Lundstrom in COVID-19, 2022
Some progress has been made on identifying specific inhibitors against Mpro. Computer models based on X-ray crystallography showed that Mpro has three functional domains. Domains one and two contain a chymotrypsin- like domain [37], implying that the alpha-ketoamide-based protease inhibitor effective against viral 3CL-family proteases [38], may be a candidate for SARS-CoV-2 as it effectively binds to Mpro [39, 40]. Additionally, Mpro contains docking sites for HIV protease inhibitors such as lopinavir, ritonavir, and saquinavir. In fact, remdesivir, the viral RNA polymerase inhibitor can also bind to the docking site [41]. Indole-based inhibitors such as GRL-1720 are known to both interact with Mpro molecularly and to inhibit the viral infectivity of cultured cells [42]. In silico analysis identified a synthetic octopeptide AT1001 (Larazotide acetate) to interact with Mpro, which showed inhibition of this protease [43]. AT1001 is an investigational drug for ARDS [43]. Many inhibitors contain a carboxyl group, commonly seen in the design of anti-HIV proteases [44]. Recently, a GC-376 analogue was discovered with inhibitory activity against Mpro. This analogue is also active against human cathepsin L, a host protease that is important for viral entry [45]. N3, a synthetic Aza-peptide Michael acceptor inhibitor, irreversibly competes with the Mpro substrate-binding site [46]. Other candidate protease inhibitors such as ebselen, disulfiram, armofur, and PX-12 are currently being tested and have shown positive binding results with Mpro [47, 48]. Given their cost-effectiveness in production, these small molecule–based protease inhibitors may prove to be beneficial candidates in treating SARS-CoV-2 in the near future.
An approach combining deep learning and molecule docking for drug discovery of cathepsin L
Published in Expert Opinion on Drug Discovery, 2023
Qi Li, Hao Wang, Wei-Li Yang, Jin-Kui Yang
Cathepsin L (CTSL) is a ubiquitously expressed endosomal cysteine protease that plays an important role in human pathobiology [1]. In patients with obesity or diabetes, serum CTSL levels are significantly higher than those in nondiabetic controls [2]. Meanwhile, CTSL deficiency protects diabetes-prone mice from insulitis and subsequent diabetes [3], suggesting that CTSL is a promising target for metabolic disorders. CTSL inhibitors can reduce body weight gain and serum insulin levels and increase glucose tolerance [2]. Meanwhile, our recent study demonstrated that CTSL is one of the drug targets for the treatment of COVID-19. CTSL inhibitors can significantly prevent SARS-CoV-2 pseudovirus infection in human cells and humanized mice (hACE2 transgenic mice) [4,5]. However, due to their toxicity and unpredictable side effects, none of these inhibitors can be used in clinical practice [6].
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).
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.
Related Knowledge Centers
- Cathepsin
- Collagen
- Cysteine Protease
- Elastin
- Protein
- Catabolism
- Lysosome
- Gene
- Papain-Like Protease
- Alpha-1 Antitrypsin