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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.
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.
The Widening Panorama of Natural Products Chemistry in Brazil
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Maria Fátima das Graças Fernandes da Silva, João Batista Fernandes, Moacir Rossi Forim, Michelli Massaroli da Silva, Jéssica Cristina Amaral
A second example of alkaloids acting as enzyme inhibitors is the acridones, which have been shown to be potent inhibitors of cathepsin V. Several natural products have been investigated for their inhibitory effects on the catalytic activity of cathepsins, and Brazilian researchers developed bioassay methodologies with these enzymes (Severino et al., 2011). Cathepsins, also known as lysosomal cysteine peptidases, are members of the papain-like peptidase family, which are implicated in many pathological conditions. These enzymes have been intensively studied as valuable targets for drug discovery and development. Although the major role of cathepsins is related to the terminal protein degradation in lysosomes, it has been shown that these enzymes are also involved in other relevant biochemical pathways, acting at selective and controlled processes with specific functions associated to their restricted tissue localization. In addition, evidence has indicated that cysteine cathepsins have specific intra- and extracellular functions, being involved in a number of diseases including cancer, osteoarthritis, osteoporosis, autoimmune disorders and viral infections. Cathepsin V was identified as a lysosomal cysteine protease specifically expressed in thymus, testis and corneal epithelium. It is believed that cathepsin V plays a role in cancer progression, thus becoming a valuable drug target for oncology.
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).
Antimicrobial peptides: A plausible approach for COVID-19 treatment
Published in Expert Opinion on Drug Discovery, 2022
Pooja Rani, Bhupinder Kapoor, Monica Gulati, Atanas G. Atanasov, Qushmua Alzahrani, Reena Gupta
Furin protease is the most abundant host protease, which is expressed in a number of cells. Despite the role of furin to SARS-CoV-2 S activation still being ambiguous, it has been widely reported to be involved in other CoV infections as well. Furin is responsible for the cleavage of S protein at polybasic S1/S2 site (PRRAR), leading to two non-covalently linked distinct sub-units [63]. The second cleavage needed for SARS-CoV-2 activation is processed by TMPRSS2, leading to release of the fusion protein of S2 [64]. Cysteine protease, cathepsin L in lysosomes has also been reported to mediate activation of S protein without any involvement of furin-mediated priming [65]. Therefore, targeting these proteases is another promising approach for treatment of COVID-19 infection.