scholarly journals Drugs, Metabolites, and Lung Accumulating Small Lysosomotropic Molecules: Multiple Targeting Impedes SARS-CoV-2 Infection and Progress to COVID-19

2021 ◽  
Vol 22 (4) ◽  
pp. 1797
Author(s):  
Markus Blaess ◽  
Lars Kaiser ◽  
Oliver Sommerfeld ◽  
René Csuk ◽  
Hans-Peter Deigner
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
Second Messengers ◽  
Cathepsin L ◽  
Host Cells ◽  
Active Metabolites ◽  
Eligibility Criteria ◽  
Pulmonary Tissue ◽  
Over The Counter ◽  
Approved Drugs

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.

scholarly journals Lysosomotropic Active Compounds—Hidden Protection against COVID-19 / SARS-CoV-2 Infection?

2020 ◽  
Author(s):  
Markus Blaess ◽  
Lars Kaiser ◽  
Martin Sauer ◽  
Hans-Peter Deigner
Keyword(s):  
Small Molecules ◽  
Viral Entry ◽  
Influenza A ◽  
Viral Infections ◽  
Cathepsin L ◽  
Disease Process ◽  
Host Cells ◽  
Promising Candidate ◽  
Lysosomal Ph ◽  
Common Skin

The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in recent decades, and it is infecting and killing increasing numbers of people every day. In this paper, we discuss the possible relationships among lysosomotropism, increasing lysosomal pH, and the SARS-CoV-2 infection and disease process, and we deduce a possible approach for treatment and prophylaxis. Lysosomotropism is a biological characteristic of small molecules, such as (hydroxyl)chloroquine, amitriptyline, NB 06, or sertraline, which is present in addition to intrinsic receptor-mediated or enzymatic pharmacological effects. Lysosomotropic compounds affect prominent inflammatory messengers, such as IL1B, CCL4, CCL20, and IL6, as well as cathepsin L dependent viral entry (fusion) into host cells. Therefore, this heterogeneous group of compounds is a promising candidate for the prevention and treatment of SARS-CoV-2 infections, as well as influenza A infections and cytokine release syndrome (CRS) triggered by bacterial or viral infections. Patients who have already taken medications with lysosomotropic compounds for other pre-existing conditions may benefit from this treatment in the COVID-19 pandemic. Increased lysosomal pH levels play an important role in the disease process in common skin disorders, such as psoriasis and atopic dermatitis, thus suggesting that affected individuals might benefit from their particular conditions in the COVID-19 pandemic. We suggest data analysis of patients with these diseases, and who are treated with lysosomotropic compounds, and, if the results are promising, subsequent clinical testing of off-label therapy with clinically approved lysosomotropic compounds in the current COVID-19 pandemic and future influenza A pandemics.

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 Aptamers in Virology—A Consolidated Review of the Most Recent Advancements in Diagnosis and Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1646
Author(s):  
Tejabhiram Yadavalli ◽  
Ipsita Volety ◽  
Deepak Shukla
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
High Specificity ◽  
Host Cells ◽  
Short Oligonucleotide ◽  
The Past ◽  
Viral Antigens ◽  
Diagnosis And Therapy ◽  
Viral Diagnosis ◽  
Made In

The use of short oligonucleotide or peptide molecules as target-specific aptamers has recently garnered substantial attention in the field of the detection and treatment of viral infections. Based on their high affinity and high specificity to desired targets, their use is on the rise to replace antibodies for the detection of viruses and viral antigens. Furthermore, aptamers inhibit intracellular viral transcription and translation, in addition to restricting viral entry into host cells. This has opened up a plethora of new targets for the research and development of novel vaccines against viruses. Here, we discuss the advances made in aptamer technology for viral diagnosis and therapy in the past decade.

scholarly journals Cathepsins: innate immune proteases that regulate viral entry into host cells

2018 ◽  
Vol 72 ◽  
pp. 253-263 ◽  
Author(s):  
Magdalena Bossowska-Nowicka ◽  
Felix N. Toka ◽  
Matylda Mielcarska ◽  
Lidia Szulc-Dąbrowska
Keyword(s):  
Viral Entry ◽  
Antigen Processing ◽  
Viral Infections ◽  
Innate Immune ◽  
Host Cells ◽  
Human Pathogens ◽  
Cellular Mechanisms ◽  
Cathepsin Proteases ◽  
Cell Adhesion And Migration

Cathepsins are group of endolysosomal proteases that regulate the mechanisms of innate and adaptive immunity, including cell adhesion and migration, antigen processing and presentation and resistance to several viral infections. Some cathepsins are required for Toll-like receptor (TLR)3, TLR7 and TLR9 cleavage and the formation of functional receptors that participate in sensing viral nucleic acids. Moreover, cathepsins directly stimulate or inhibit cytokine secretion involved in the regulation of antiviral innate immune response. Recent findings underline the important role of cathepsins in the entry of filoviruses, reoviruses, retroviruses and other types of viruses into the host cell. Many enveloped viruses require the presence of cathepsins for efficient fusion with membranes of infected cells, and the inhibition of their activity results in a significant reduction of virus replication. In addition, many viruses utilize conserved cellular mechanisms, such as endocytosis or low pH within the endosome, for efficient penetration into the cell interior, disassembly of viral capsid, and other stages of productive viral replication cycle. Therefore, a better understanding of the functional role of cathepsin proteases in the pathogenesis of viral infections should lead to the development of novel therapeutics for a variety of particularly dangerous human pathogens.

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 SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells

2020 ◽  
Vol 21 (16) ◽  
pp. 5707 ◽  
Author(s):  
Rolando Cannalire ◽  
Irina Stefanelli ◽  
Carmen Cerchia ◽  
Andrea R. Beccari ◽  
Sveva Pelliccia ◽  
...  
Keyword(s):  
Small Molecules ◽  
Viral Entry ◽  
Viral Infections ◽  
Host Factors ◽  
Host Cells ◽  
S Protein ◽  
Entry Inhibitors ◽  
Heptad Repeats ◽  
Direct Acting ◽  
Complementary Strategy

The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.

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 HIV protease inhibitors saquinavir and nelfinavir are potent inhibitors of cathepsin L activity: A potential treatment for COVID-19 patients

2020 ◽  
Author(s):  
Marcelo Freitas Montenegro ◽  
Yousef Al-Abed ◽  
Mingzhu He ◽  
Kevin J. Tracey ◽  
Timothy R. Billiar
Keyword(s):  
Clinical Trials ◽  
Cathepsin L ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Potential Treatment ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract The 2019 coronavirus disease pandemic (COVID-19) has mobilized efforts worldwide, and several ongoing clinical trials aimed at developing a drug-based treatment for its control. Cathepsin L is an endosomal cysteine protease that mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells and viruses/host cell endosome membrane fusion. Therefore, cathepsin L is a potential target for the treatment of COVID-19 patients. In this report, we describe a previously unknown inhibitory effect of two FDA-approved drugs, saquinavir and nelfinavir, on human cathepsin L activity. Whether the pivotal role for cathepsin L in Sars-Cov-2 infection described in vitro can be translated to humans, our results support immediate clinical trials of saquinavir or nelfinavir as a potential treatment for COVID-19 patients.

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).

scholarly journals A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients

2020 ◽  
Author(s):  
Dharmendra Kumar Maurya
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Viral Entry ◽  
Virus Disease ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Host Immune System ◽  
Main Protease ◽  
Approved Drugs

<p></p><p>The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.</p><p></p>

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