CTSL bind CTSL inhibitors

Stable Identifier
R-HSA-9685655
Type
Reaction [binding]
Species
Homo sapiens
Compartment
endocytic vesicle lumen
ReviewStatus
5/5
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CTSL bind CTSL inhibitors
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Lysosomes play critical roles in human biology receiving, trafficking, processing, and degrading biological molecules from cellular processes such as endocytosis, phagocytosis, autophagy and secretion. Lysosomes house around sixty proteolytic enzymes, among them cathepsins. Cathepsins are involved in many processes involving cell death, protein degradation, post-translational modifications of proteins, extracellular matrix (ECM) remodeling, autophagy, and immune signaling. The early stages of the viral life cycle involve the cleavage of the viral spike protein by cathepsin L (CTSL) in late endosomes, facilitating viral RNA release to continue viral replication. Teicoplanin, a glycopeptide antibiotic used to treat Gram-positive bacterial infection, especially in Staphylococcal infections, was shown to have efficacy in vitro against Ebola Virus, MERS and SARS-CoV-1 (Zhou et al. 2016).

Teicoplanin is thought to inhibit the low pH cleavage of the viral spike protein by CTSL in late endosomes thereby preventing the release of genomic viral RNA and the continuation of virus replication cycle (Baron et al. 2020). The target sequence that serve as the cleavage site for CTSL is conserved in the SARS-CoV-2 spike protein (Zhou et al. 2020 [preprint]). Further investigation is required to determine the therapeutic potential of teicoplanin in COVID-19 patients.

Relacatib is an investigational drug trialed for the treatment of osteoporosis (Duong et al. 2016). It is a potent CTSK inhibitor but also shows activity against CTSL (Kumar et al. 2007) so could potentially be investigated for Covid-19 patients. The antileprotic drug clofazimine and the antituberculous drugs rifampicin and isoniazid have been shown to inhibit cathepsins B, H and L from purified goat and bovine brains (Kamboj et al. 2003).
Literature References
PubMed ID Title Journal Year
33774649 Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

Zhao, MM, Yang, WL, Yang, FY, Zhang, L, Huang, WJ, Hou, W, Fan, CF, Jin, RH, Feng, YM, Wang, YC, Yang, JK

Signal Transduct Target Ther 2021
23105391 Effects of some antituberculous and anti-leprotic drugs on cathepsins B, H and L

Kamboj, RC, Raghav, N, Mittal, A, Khurana, S, Sadana, R, Singh, H

Indian J Clin Biochem 2003
26953343 Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)

Zhou, N, Pan, T, Zhang, J, Li, Q, Zhang, X, Bai, C, Huang, F, Peng, T, Zhang, J, Liu, C, Tao, L, Zhang, H

J. Biol. Chem. 2016
32179150 Teicoplanin: an alternative drug for the treatment of COVID-19?

Baron, SA, Devaux, C, Colson, P, Raoult, D, Rolain, JM

Int. J. Antimicrob. Agents 2020
16962401 A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys

Kumar, S, Dare, L, Vasko-Moser, JA, James, IE, Blake, SM, Rickard, DJ, Hwang, SM, Tomaszek, T, Yamashita, DS, Marquis, RW, Oh, H, Jeong, JU, Veber, DF, Gowen, M, Lark, MW, Stroup, G

Bone 2007
Participants
Input
Output
Participates
as an event of
Authored
Gillespie, ME  (2020-09-09)
Reviewed
Acencio, ML  (2020-09-09)
Created
Jassal, B  (2020-04-24)
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