scholarly journals Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 192 ◽  
Author(s):  
Markus Hoffmann ◽  
Svenja Victoria Kaufmann ◽  
Carina Fischer ◽  
Wiebke Maurer ◽  
Anna-Sophie Moldenhauer ◽  
...  
Keyword(s):  
Viral Entry ◽  
Ebola Virus ◽  
Mutational Analysis ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Host Cells ◽  
Single Amino Acid ◽  
Limited Information ◽  
Cysteine Cathepsins ◽  
Ebov Infection

Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser degree, cathepsin L (CatL), at least in most cell culture systems. However, there is limited information on whether and how EBOV-GP can acquire resistance to CatB/L inhibitors. Here, we addressed this question using replication-competent vesicular stomatitis virus bearing EBOV-GP. Five passages of this virus in the presence of the CatB/CatL inhibitor MDL28170 were sufficient to select resistant viral variants and sequencing revealed that all GP sequences contained a V37A mutation, which, in the context of native GP, is located in the base of the GP surface unit. In addition, some GP sequences harbored mutation S195R in the receptor-binding domain. Finally, mutational analysis demonstrated that V37A but not S195R conferred resistance against MDL28170 and other CatB/CatL inhibitors. Collectively, a single amino acid substitution in GP is sufficient to confer resistance against CatB/CatL inhibitors, suggesting that usage of CatB/CatL inhibitors for antiviral therapy may rapidly select for resistant viral variants.

scholarly journals Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19

2020 ◽  
Author(s):  
Kas Steuten ◽  
Heeyoung Kim ◽  
John C. Widen ◽  
Brett M. Babin ◽  
Ouma Onguka ◽  
...  
Keyword(s):  
Viral Entry ◽  
Therapeutic Strategy ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Development Programs ◽  
Entry Pathway ◽  
Cysteine Cathepsins ◽  
Human Cathepsin ◽  
Transmembrane Serine Protease ◽  
Substantial Drop

ABSTRACTTwo proteases produced by the SARS-CoV-2 virus, Mpro and PLpro, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mpro and PLpro proteases. These efforts identified a small number of hits for the Mpro protease and no viable hits for the PLpro protease. Of the Mpro hits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead Mpro inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mpro inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting Mpro and PLpro proteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.

scholarly journals COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks

2020 ◽  
Vol 21 (14) ◽  
pp. 4953 ◽  
Author(s):  
Markus Blaess ◽  
Lars Kaiser ◽  
Martin Sauer ◽  
René Csuk ◽  
Hans-Peter Deigner
Keyword(s):  
Viral Entry ◽  
Cathepsin L ◽  
Treatment Strategies ◽  
Disease Process ◽  
Host Cells ◽  
Cytokine Release ◽  
Early Administration ◽  
Lysosomal Ph ◽  
New Treatment ◽  
Exposure Prophylaxis

In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide. SARS-CoV-2 infection/COVID-19 provides numerous therapeutic targets, each of them promising, but not leading to the success of therapy to date. Neither an antiviral nor an immunomodulatory therapy in patients with SARS-CoV-2 infection/COVID-19 or pre-exposure prophylaxis against SARS-CoV-2 has proved to be effective. In this review, we try to close the gap and point out the likely relationships among lysosomotropism, increasing lysosomal pH, SARS-CoV-2 infection, and disease process, and we deduce an approach for the treatment and prophylaxis of COVID-19, and cytokine release syndrome (CRS)/cytokine storm triggered by bacteria or viruses. Lysosomotropic compounds affect prominent inflammatory messengers (e.g., IL-1B, CCL4, CCL20, and IL-6), cathepsin-L-dependent viral entry of host cells, and products of lysosomal enzymes that promote endothelial stress response in systemic inflammation. As supported by recent clinical data, patients who have already taken lysosomotropic drugs for other pre-existing conditions likely benefit from this treatment in the COVID-19 pandemic. The early administration of a combination of antivirals such as remdesivir and lysosomotropic drugs, such as the antibiotics teicoplanin or dalbavancin, seems to be able to prevent SARS-CoV-2 infection and transition to COVID-19.

scholarly journals Identification and biochemical characterisation of Acanthamoeba castellanii cysteine protease 3

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Zhixin Wang ◽  
Duo Wu ◽  
Hiroshi Tachibana ◽  
Meng Feng ◽  
Xun-jia Cheng
Keyword(s):  
Cathepsin L ◽  
Mrna Level ◽  
Acanthamoeba Castellanii ◽  
Cysteine Proteases ◽  
Hydrolytic Activity ◽  
Negative Control ◽  
Host Cells ◽  
Signalling Pathways ◽  
Corneal Epithelial ◽  
Biochemical Characterisation

Abstract Background Acanthamoeba spp. are free-living amoeba that are ubiquitously distributed in the environment. This study examines pathogenic Acanthamoeba cysteine proteases (AcCPs) belonging to the cathepsin L-family and explores the mechanism of AcCP3 interaction with host cells. Methods Six AcCP genes were amplified by polymerase chain reaction (PCR). Quantitative real-time PCR was used to analyse the relative mRNA expression of AcCPs during the encystation process and between pre- and post-reactivated trophozoites. To further verify the role of AcCP3 in these processes, AcCP3 recombinant proteins were expressed in Escherichia coli, and the hydrolytic activity of AcCP3 was determined. The influence of the AcCP3 on the hydrolytic activity of trophozoites and the toxicity of trophozoites to human corneal epithelial cells (HCECs) was examined by inhibiting AcCP3 expression using siRNA. Furthermore, the levels of p-Raf and p-Erk were examined in HCECs following coculture with AcCP3 gene knockdown trophozoites by Western blotting. Results During encystation, five out of six AcCPs exhibited decreased expression, and only AcCP6 was substantially up-regulated at the mRNA level, indicating that most AcCPs were not directly correlated to encystation. Furthermore, six AcCPs exhibited increased expression level following trophozoite reactivation with HEp-2 cells, particularly AcCP3, indicating that these AcCPs might be virulent factors. After refolding of recombinant AcCP3 protein, the 27 kDa mature protein from the 34 kDa pro-protein hydrolysed host haemoglobin, collagen and albumin and showed high activity in an acidic environment. After AcCP3 knockdown, the hydrolytic activity of trophozoite crude protein against gelatin was decreased, suggesting that these trophozoites had decreased toxicity. Compared with untreated trophozoites or negative control siRNA-treated trophozoites, AcCP3-knockdown trophozoites were less able to penetrate and damage monolayers of HCECs. Western blot analysis showed that the activation levels of the Ras/Raf/Erk/p53 signalling pathways in HCECs decreased after inhibiting the expression of trophozoite AcCP3. Conclusions AcCP6 was correlated to encystation. Furthermore, AcCP3 was a virulent factor in trophozoites and participated in the activation of the Ras/Raf/Erk/p53 signalling pathways of host cells.

scholarly journals After one year of the COVID-19 pandemic and hundreds of suggested drugs, will cathepsin L inhibitors be the solution?

Avicenna ◽  
2021 ◽  
Vol 2022 (1) ◽  
Author(s):  
Amr Ahmed ◽  
Mohammad Nezami ◽  
Abdullah Alkattan ◽  
Ahmed Mohamed ◽  
Omar Alshazly ◽  
...  
Keyword(s):  
Active Sites ◽  
Viral Infections ◽  
Cathepsin L ◽  
Docking Studies ◽  
Host Cells ◽  
Endosomal Membrane ◽  
Cysteine Cathepsins ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin ◽  
One Year

Cysteine cathepsins are defined as lysosomal enzymes that are members of the papain family. Cysteine cathepsins (Cts) prevalently exist in whole organisms, varying from prokaryotes to mammals, and possess greatly conserved cysteine residues in their active sites. Cts are engaged in the digestion of cellular proteins, activation of zymogens, and remodeling of the extracellular matrix (ECM). Host cells are entered by SARS-CoV-2 via endocytosis. Cathepsin L and phosphatidylinositol 3-phosphate 5-kinase are crucial in endocytosis by cleaving the spike protein, which permits viral membrane fusion with the endosomal membrane and succeeds in the release of the viral genome to the host cell. Therefore, inhibition of cathepsin L may be advantageous in terms of decreasing infection caused by SARS-CoV-2. Coordinate inhibition of multiple Cts and lysosomal function by different drugs and biological agents might be of value for some purposes, such as a parasite or viral infections and antineoplastic applications. Zn2+ deficiency or dysregulation leads to exaggerated cysteine cathepsin activity, increasing the autoimmune/inflammatory response. For this purpose, Zn2+ metal can be safely combined with a drug that increases the anti-proteolytic effect of endogenous Zn2+, lowering the excessive activity of some CysCts. Biguanide derivative complexes with Zn2+ have been found to be promising inhibitors of CysCts protease reactions. Molecular docking studies of cathepsin L inhibited by the metformin-Zn+2 complex have been performed, showing two strong key interactions (Cys-25&His-163) and an extra H-bond with Asp-163 compared to cocrystallized Zn+2 (PDB ID 4axl).

scholarly journals Identification and biochemical characterisation of Acanthamoeba castellanii cysteine protease 3

2020 ◽  
Author(s):  
Zhixin Wang ◽  
Duo Wu ◽  
Hiroshi Tachibana ◽  
Meng Feng ◽  
Xunjia Cheng
Keyword(s):  
Cathepsin L ◽  
Mrna Level ◽  
Acanthamoeba Castellanii ◽  
Cysteine Proteases ◽  
Hydrolytic Activity ◽  
Negative Control ◽  
Host Cells ◽  
Signalling Pathways ◽  
Corneal Epithelial ◽  
Biochemical Characterisation

Abstract Background: Acanthamoeba spp. are free-living amoeba that are ubiquitously distributed in the environment. This study examines pathogenic Acanthamoeba cysteine proteases (AcCPs) belonging to the cathepsin L-family and explores the mechanism of AcCP3 interaction with host cells.Methods: Six AcCP genes were amplified by PCR. Quantitative real-time polymerase chain reaction was used to analyse the relative mRNA expression of AcCPs during the encystation process, and between pre- and post-reactivated trophozoites. To further verify the role of AcCP3 in these processes, AcCP3 recombinant proteins were expressed in Escherichia coli, and the hydrolytic activity of AcCP3 was determined. The influence of the AcCP3 on the hydrolytic activity of trophozoites and the toxicity of trophozoites to human corneal epithelial cells (HCECs) was examined by inhibiting AcCP3 expression using siRNA. Further, the levels of p-Raf and p-Erk were examined in HCECs following coculture with AcCP3 gene knockdown trophozoites by western blotting.Results: During encystment, five out of six AcCPs exhibited decreased expression, and only AcCP6 was substantially up-regulated at the mRNA level, indicating that most AcCPs were not directly correlated to encystation. Further, six AcCPs exhibited increased expression level following trophozoite reactivation with HEp2 cells, particularly AcCP3, indicating that these AcCPs might be virulent factors. After refolding the AcCP3 recombinant protein, the 27 kDa mature protein from the 34 kDa pro-protein hydrolysed host haemoglobin, collagen and albumin, and showed high activity in an acidic environment. After AcCP3 knockdown, the hydrolysis activity of trophozoite crude protein against gelatin was decreased, suggesting that these trophozoite had decreased toxicity. Compared with untreated trophozoites or negative control siRNA-treated trophozoites, AcCP3-knockdown trophozoites were less able to penetrate and damage monolayers of HCECs. Western blot analysis showed that after inhibiting the expression of trophozoite AcCP3, the activation levels of the Ras/Raf/Erk/p53 signalling pathways in HCECs were decreased.Conclusions: AcCP6 was correlated to encystation. Further, AcCP3 is a virulent factor in trophozoites, and participated in the activation of the Ras/Raf/Erk/p53 signalling pathways of host cells.

scholarly journals A Virion-Based Assay for Glycoprotein Thermostability Reveals Key Determinants of Filovirus Entry and Its Inhibition

2020 ◽  
Vol 94 (18) ◽  
Author(s):  
Robert H. Bortz ◽  
Anthony C. Wong ◽  
Michael G. Grodus ◽  
Hannah S. Recht ◽  
Marc C. Pulanco ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
Viral Entry ◽  
Ebola Virus ◽  
Elevated Temperatures ◽  
Vaccine Development ◽  
Cysteine Proteases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Temperature Dependent ◽  
Acid Ph

ABSTRACT Ebola virus (EBOV) entry into cells is mediated by its spike glycoprotein (GP). Following attachment and internalization, virions traffic to late endosomes where GP is cleaved by host cysteine proteases. Cleaved GP then binds its cellular receptor, Niemann-Pick C1. In response to an unknown cellular trigger, GP undergoes conformational rearrangements that drive fusion of viral and endosomal membranes. The temperature-dependent stability (thermostability) of the prefusion conformers of class I viral fusion glycoproteins, including those of filovirus GPs, has provided insights into their propensity to undergo fusion-related rearrangements. However, previously described assays have relied on soluble glycoprotein ectodomains. Here, we developed a simple enzyme-linked immunosorbent assay (ELISA)-based assay that uses the temperature-dependent loss of conformational epitopes to measure thermostability of GP embedded in viral membranes. The base and glycan cap subdomains of all filovirus GPs tested suffered a concerted loss of prefusion conformation at elevated temperatures but did so at different temperature ranges, indicating virus-specific differences in thermostability. Despite these differences, all of these GPs displayed reduced thermostability upon cleavage to GP conformers (GPCL). Surprisingly, acid pH enhanced, rather than decreased, GP thermostability, suggesting it could enhance viral survival in hostile endo/lysosomal compartments. Finally, we confirmed and extended previous findings that some small-molecule inhibitors of filovirus entry destabilize EBOV GP and uncovered evidence that the most potent inhibitors act through multiple mechanisms. We establish the epitope-loss ELISA as a useful tool for studies of filovirus entry, engineering of GP variants with enhanced stability for use in vaccine development, and discovery of new stability-modulating antivirals. IMPORTANCE The development of Ebola virus countermeasures is challenged by our limited understanding of cell entry, especially at the step of membrane fusion. The surface-exposed viral protein, GP, mediates membrane fusion and undergoes major structural rearrangements during this process. The stability of GP at elevated temperatures (thermostability) can provide insights into its capacity to undergo these rearrangements. Here, we describe a new assay that uses GP-specific antibodies to measure GP thermostability under a variety of conditions relevant to viral entry. We show that proteolytic cleavage and acid pH have significant effects on GP thermostability that shed light on their respective roles in viral entry. We also show that the assay can be used to study how small-molecule entry inhibitors affect GP stability. This work provides a simple and readily accessible assay to engineer stabilized GP variants for antiviral vaccines and to discover and improve drugs that act by modulating GP stability.

scholarly journals Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases

2015 ◽  
Vol 60 (2) ◽  
pp. 797-805 ◽  
Author(s):  
Caroline Schad ◽  
Ulrike Baum ◽  
Benjamin Frank ◽  
Uwe Dietzel ◽  
Felix Mattern ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Neglected Tropical Diseases ◽  
Cathepsin L ◽  
Selective Inhibition ◽  
Cysteine Proteases ◽  
Host Cells ◽  
Th2 Response ◽  
Content Type

ABSTRACTLeishmaniasis is one of the major neglected tropical diseases of the world. Druggable targets are the parasite cysteine proteases (CPs) of clan CA, family C1 (CAC1). In previous studies, we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylate compounds 13b and 13e, in a series of inhibitors of the cathepsin L (CL) subfamily of the papain clan CAC1. Both displayed antileishmanial activityin vitrowhile not showing cytotoxicity against host cells. In further investigations, the mode of action was characterized inLeishmania major. It was demonstrated that aziridines 13b and 13e mainly inhibited the parasitic cathepsin B (CB)-like CPC enzyme and, additionally, mammalian CL. Although these compounds induced cell death ofLeishmaniapromastigotes and amastigotesin vitro, the induction of a proleishmanial T helper type 2 (Th2) response caused by host CL inhibition was observedin vivo. Therefore, we describe here the synthesis of a new library of more selective peptidomimetic aziridine-2,3-dicarboxylates discriminating between host and parasite CPs. The new compounds are based on 13b and 13e as lead structures. One of the most promising compounds of this series is compound s9, showing selective inhibition of the parasite CPsLmaCatB (a CB-like enzyme ofL. major; also namedL. majorCPC) andLmCPB2.8 (a CL-like enzyme ofLeishmania mexicana) while not affecting mammalian CL and CB. It displayed excellent leishmanicidal activities againstL. majorpromastigotes (50% inhibitory concentration [IC50] = 37.4 μM) and amastigotes (IC50= 2.3 μM). In summary, we demonstrate a new selective aziridine-2,3-dicarboxylate, compound s9, which might be a good candidate for futurein vivostudies.

scholarly journals Enhancement of Ebola Virus Infection via Ficolin-1 Interaction with the Mucin Domain of GP Glycoprotein

2016 ◽  
Vol 90 (11) ◽  
pp. 5256-5269 ◽  
Author(s):  
Anne-Laure Favier ◽  
Evelyne Gout ◽  
Olivier Reynard ◽  
Olivier Ferraris ◽  
Jean-Philippe Kleman ◽  
...  
Keyword(s):  
Virus Infection ◽  
Ebola Virus ◽  
Mannose Binding Lectin ◽  
Innate Immune ◽  
Host Cells ◽  
Target Cells ◽  
Viral Glycoprotein ◽  
Mannose Binding ◽  
Ebov Infection ◽  
Binding Lectin

ABSTRACTEbola virus infection requires the surface viral glycoprotein to initiate entry into the target cells. The trimeric glycoprotein is a highly glycosylated viral protein which has been shown to interact with host C-type lectin receptors and the soluble complement recognition protein mannose-binding lectin, thereby enhancing viral infection. Similarly to mannose-binding lectin, ficolins are soluble effectors of the innate immune system that recognize particular glycans at the pathogen surface. In this study, we demonstrate that ficolin-1 interacts with the Zaire Ebola virus (EBOV) glycoprotein, and we characterized this interaction by surface plasmon resonance spectroscopy. Ficolin-1 was shown to bind to the viral glycoprotein with a high affinity. This interaction was mediated by the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of the viral glycoprotein. Using a ficolin-1 control mutant devoid of sialic acid-binding capacity, we identified sialylated moieties of the mucin domain to be potential ligands on the glycoprotein. In cell culture, using both pseudotyped viruses and EBOV, ficolin-1 was shown to enhance EBOV infection independently of the serum complement. We also observed that ficolin-1 enhanced EBOV infection on human monocyte-derived macrophages, described to be major viral target cells,. Competition experiments suggested that although ficolin-1 and mannose-binding lectin recognized different carbohydrate moieties on the EBOV glycoprotein, the observed enhancement of the infection likely depended on a common cellular receptor/partner. In conclusion, ficolin-1 could provide an alternative receptor-mediated mechanism for enhancing EBOV infection, thereby contributing to viral subversion of the host innate immune system.IMPORTANCEA specific interaction involving ficolin-1 (M-ficolin), a soluble effector of the innate immune response, and the glycoprotein (GP) of EBOV was identified. Ficolin-1 enhanced virus infection instead of tipping the balance toward its elimination. An interaction between the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of Ebola virus GP occurred. In this model, the enhancement of infection was shown to be independent of the serum complement. The facilitation of EBOV entry into target host cells by the interaction with ficolin-1 and other host lectins shunts virus elimination, which likely facilitates the survival of the virus in infected host cells and contributes to the virus strategy to subvert the innate immune response.

scholarly journals Biochemical and Structural Characterization of Cathepsin L-Processed Ebola Virus Glycoprotein: Implications for Viral Entry and Immunogenicity

2010 ◽  
Vol 84 (6) ◽  
pp. 2972-2982 ◽  
Author(s):  
Chantelle L. Hood ◽  
Jonathan Abraham ◽  
Jeffrey C. Boyington ◽  
Kwanyee Leung ◽  
Peter D. Kwong ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Cathepsin L ◽  
Neutralizing Antibody ◽  
Cellular Attachment ◽  
Conserved Core ◽  
Virion Surface

ABSTRACT Ebola virus (EBOV) cellular attachment and entry is initiated by the envelope glycoprotein (GP) on the virion surface. Entry of this virus is pH dependent and associated with the cleavage of GP by proteases, including cathepsin L (CatL) and/or CatB, in the endosome or cell membrane. Here, we characterize the product of CatL cleavage of Zaire EBOV GP (ZEBOV-GP) and evaluate its relevance to entry. A stabilized recombinant form of the EBOV GP trimer was generated using a trimerization domain linked to a cleavable histidine tag. This trimer was purified to homogeneity and cleaved with CatL. Characterization of the trimeric product by N-terminal sequencing and mass spectrometry revealed three cleavage fragments, with masses of 23, 19, and 4 kDa. Structure-assisted modeling of the cathepsin L-cleaved ZEBOV-GP revealed that cleavage removes a glycosylated glycan cap and mucin-like domain (MUC domain) and exposes the conserved core residues implicated in receptor binding. The CatL-cleaved ZEBOV-GP intermediate bound with high affinity to a neutralizing antibody, KZ52, and also elicited neutralizing antibodies, supporting the notion that the processed intermediate is required for viral entry. Together, these data suggest that CatL cleavage of EBOV GP exposes its receptor-binding domain, thereby facilitating access to a putative cellular receptor in steps that lead to membrane fusion.

scholarly journals After one year of COVID-19 Pandemic and Hundreds of Suggested Drugs, Will Cathepsin L Inhibitors be the Solution?

2021 ◽  
Author(s):  
Amr Kamel Khalil Ahmed
Keyword(s):  
Viral Infections ◽  
Cathepsin L ◽  
Docking Studies ◽  
Cellular Protein ◽  
Host Cells ◽  
Protein Activation ◽  
Endosomal Membrane ◽  
Cysteine Cathepsins ◽  
One Year ◽  
Remodeling Of Extracellular Matrix

Cysteine cathepsins are defined as lysosomal enzymes which are member of the papain family. Cysteine cathepsins (Cts) prevalently exist in whole organisms varying from prokaryotes to mammals and possess in their active site greatly conserved residue of cysteine. Cts are engaged in the digestion of cellular protein, activation of zymogen, and remodeling of extracellular matrix (ECM). Host cells are entered by SARS-CoV-2 via endocytosis. Cathepsin L and phosphatidylinositol 3-phosphate 5-kinase are crucial in terms of the endocytosis by cleaving the spike protein, which permits viral membrane fusion with endosomal membrane, and succeeded by the releasing of viral genome to the host cell. Thereby, inhibition of cathepsin L may be advantageous in terms of decreasing infection caused by SARS-CoV-2. Coordinate inhibition of multiple Cts and lysosomal function by different drugs and biological agents might be of value for some purposes such as parasite or viral infections and anti-neoplastic applications. It has been found that Zn 2+ deficiency or dysregulation leads to an exaggerated activity of Cysteine cathepsin increasing the autoimmune/inflammatory response. At this purpose Zn 2+ metal can be safely combined with a drug that increases the anti-proteolytic effect of endogenous Zn 2+ lowering the excessive activity of some CysCts. Biguanide derivatives complex with Zn 2+ have been found to be promising inhibitors of CysCts protease reactions. Molecular docking studies of Cathepsin L Inhibited by Metformin-Zn+2 complex have been performed showing two strong key interactions ( Cys-25&His-163) and an extra H-bond with Asp-163 compared to the co-crystallized Zn +2 (PDB ID 4axl).

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