scholarly journals SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors

2019 ◽  
Vol 29 (22) ◽  
pp. 126620 ◽  
Author(s):  
Michael B. Plewe ◽  
Landon R. Whitby ◽  
Shibani Naik ◽  
Eric R. Brown ◽  
Nadezda V. Sokolova ◽  
...  
Keyword(s):  
Cell Entry ◽  
Entry Inhibitors ◽  
Sar Studies

scholarly journals Characterization of SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 on cell entry, host range, and sensitivity to convalescent plasma and ACE2 decoy receptor

2021 ◽  
Author(s):  
Wenlin Ren ◽  
Xiaohui Ju ◽  
Mingli Gong ◽  
Jun Lan ◽  
Yanying Yu ◽  
...  
Keyword(s):  
Host Range ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Cell Entry ◽  
Decoy Receptor ◽  
Host Tropism ◽  
Entry Inhibitors ◽  
Rapid Spread ◽  
Entry Efficiency

ABSTRACTRecently, highly transmissible SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 were identified in India with mutations within the spike proteins. The spike protein of Kappa contains four mutations E154K, L452R, E484Q and P681R, and Delta contains L452R, T478K and P681R, while B.1.618 spike harbors mutations Δ145-146 and E484K. However, it remains unknown whether these variants have altered in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies as well as entry inhibitors. In this study, we found that Kappa, Delta or B.1.618 spike uses human ACE2 with no or slightly increased efficiency, while gains a significantly increased binding affinity with mouse, marmoset and koala ACE2 orthologs, which exhibits limited binding with WT spike. Furthermore, the P618R mutation leads to enhanced spike cleavage, which could facilitate viral entry. In addition, Kappa, Delta and B.1.618 exhibits a reduced sensitivity to neutralization by convalescent sera owning to the mutation of E484Q, T478K, Δ145-146 or E484K, but remains sensitive to entry inhibitors-ACE2-lg decoy receptor. Collectively, our study revealed that enhanced human and mouse ACE2 receptor engagement, increased spike cleavage and reduced sensitivity to neutralization antibodies of Kappa, Delta and B.1.618 may contribute to the rapid spread of these variants and expanded host range. Furthermore, our result also highlighted that ACE2-lg could be developed as broad-spectrum antiviral strategy against SARS-CoV-2 variants.

scholarly journals Characterization of lassa virus cell entry inhibitors: Determination of the active enantiomer by asymmetric synthesis

2009 ◽  
Vol 19 (14) ◽  
pp. 3771-3774 ◽  
Author(s):  
Landon R. Whitby ◽  
Andrew M. Lee ◽  
Stefan Kunz ◽  
Michael B.A. Oldstone ◽  
Dale L. Boger
Keyword(s):  
Asymmetric Synthesis ◽  
Cell Entry ◽  
Lassa Virus ◽  
Entry Inhibitors

scholarly journals Clinically Approved Ion Channel Inhibitors Close Gates for Hepatitis C Virus and Open Doors for Drug Repurposing in Infectious Viral Diseases

2016 ◽  
Vol 91 (2) ◽  
Author(s):  
Thomas Pietschmann
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Cell Entry ◽  
Severe Liver ◽  
Entry Inhibitors ◽  
Chronic Hepatitis C Virus ◽  
Severe Liver Disease ◽  
Limit Access

ABSTRACT Chronic hepatitis C virus (HCV) infection causes severe liver disease and affects ca. 146 million individuals. Novel directly acting antivirals targeting HCV have revolutionized treatment. However, high costs limit access to therapy. Recently, several related drugs used in humans to treat allergies or as neuroleptics emerged as potent HCV cell entry inhibitors. Insights into their antiviral modes of action may increase opportunities for drug repurposing in hepatitis C and possibly other important human viral infections.

scholarly journals Rapid Dissociation of HIV-1 from Cultured Cells Severely Limits Infectivity Assays, Causes the Inactivation Ascribed to Entry Inhibitors, and Masks the Inherently High Level of Infectivity of Virions

2009 ◽  
Vol 84 (6) ◽  
pp. 3106-3110 ◽  
Author(s):  
Emily J. Platt ◽  
Susan L. Kozak ◽  
James P. Durnin ◽  
Thomas J. Hope ◽  
David Kabat
Keyword(s):  
Immunofluorescence Microscopy ◽  
Cultured Cells ◽  
Cell Entry ◽  
Inhibitory Effects ◽  
Entry Inhibitors ◽  
Ccr5 Antagonists ◽  
High Level ◽  
Hiv 1

ABSTRACT By using immunofluorescence microscopy to observe and analyze freshly made HIV-1 virions adsorbed onto cells, we found that they are inherently highly infectious, rather than predominantly defective as previously suggested. Surprisingly, polycations enhance titers 20- to 30-fold by stabilizing adsorption and preventing a previously undescribed process of rapid dissociation, strongly implying that infectivity assays for many viruses are limited not only by inefficient virus diffusion onto cells but also by a postattachment race between entry and dissociation. This kinetic competition underlies inhibitory effects of CCR5 antagonists and explains why adaptive HIV-1 mutations overcome many cell entry limitations by accelerating entry.

Development and Evaluation of a FACS-Based Medium-Throughput Assay for HCV Entry Inhibitors

2009 ◽  
Vol 14 (6) ◽  
pp. 620-626 ◽  
Author(s):  
Sigrid Ziegler ◽  
Bernd Kronenberger ◽  
Beatrice A.-M. Albrecht ◽  
Artur Kaul ◽  
Anna-Lena Gamer ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
Basic Research ◽  
Cell Entry ◽  
Luciferase Reporter ◽  
Human Hepatoma ◽  
Screening System ◽  
Human Hepatoma Cells ◽  
Entry Inhibitors ◽  
Fast Screening ◽  
Key Events

The interaction between the hepatitis C virus (HCV) envelope glycoprotein E2 and the human tetraspanin protein CD81 is one of the key events involved in HCV cell entry. Therefore, compounds that interfere with this interaction may be useful tools for basic research and potential drugs for the treatment of HCV infection. The authors describe a medium-throughput assay for ligands of the E2 binding site on the CD81 receptor. In the assay, human hepatoma cells are incubated with the test compounds and stained with a fluorescently labeled anti-CD81 antibody (JS81). Flow cytometry is used to detect the level of bound antibody, reflecting the inhibitory potencies of the compounds. Eighty percent of compounds active in the assay show efficacy in an infection assay using luciferase reporter genome in cell culture. Thus, the assay can be used as a fast screening system for inhibitors of interaction of viral E2 to host cell CD81-LELs. ( Journal of Biomolecular Screening 2009;620-626)

scholarly journals Identifying SARS-CoV-2 entry inhibitors through drug repurposing screens of SARS-S and MERS-S pseudotyped particles

2020 ◽  
Author(s):  
Catherine Z. Chen ◽  
Miao Xu ◽  
Manisha Pradhan ◽  
Kirill Gorshkov ◽  
Jennifer Petersen ◽  
...  
Keyword(s):  
High Throughput ◽  
Broad Spectrum ◽  
Vaccine Development ◽  
Drug Repurposing ◽  
Cell Entry ◽  
Entry Inhibitors ◽  
Small Molecule Drugs ◽  
Global Pandemic ◽  
Initial Stage ◽  
Approved Drugs

AbstractWhile vaccine development will hopefully quell the global pandemic of COVID-19 caused by SARS-CoV-2, small molecule drugs that can effectively control SARS-CoV-2 infection are urgently needed. Here, inhibitors of spike (S) mediated cell entry were identified in a high throughput screen of an approved drugs library with SARS-S and MERS-S pseudotyped particle entry assays. We discovered six compounds (cepharanthine, abemaciclib, osimertinib, trimipramine, colforsin, and ingenol) to be broad spectrum inhibitors for spike-mediated entry. This work should contribute to the development of effective treatments against the initial stage of viral infection, thus reducing viral burden in COVID-19 patients.Abstract Figure

scholarly journals Naturally Occurring Variability in the Envelope Glycoprotein of HIV-1 and Development of Cell Entry Inhibitors

Biochemistry ◽  
2010 ◽  
Vol 49 (11) ◽  
pp. 2359-2367 ◽  
Author(s):  
Evan T. Brower ◽  
Arne Schön ◽  
Ernesto Freire
Keyword(s):  
Envelope Glycoprotein ◽  
Cell Entry ◽  
Entry Inhibitors ◽  
Naturally Occurring ◽  
Hiv 1

scholarly journals A Graph Convolutional Network-based screening strategy for rapid identification of SARS-CoV-2 cell-entry inhibitors

2021 ◽  
Author(s):  
Peng Gao ◽  
Miao Xu ◽  
Qi Zhang ◽  
Catherine Chen ◽  
Hui Guo ◽  
...  
Keyword(s):  
Drug Targets ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Screening Strategy ◽  
Cell Entry ◽  
Classification Model ◽  
Convolutional Network ◽  
Entry Inhibitors ◽  
Drug Identification ◽  
Conventional Drug

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time-consuming and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in ~2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets.

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