scholarly journals Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses in cell culture

2020 ◽  
Author(s):  
Yanmei Hu ◽  
Chunlong Ma ◽  
Tommy Szeto ◽  
Brett Hurst ◽  
Bart Tarbet ◽  
...  
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Cathepsin L ◽  
Antiviral Drug ◽  
Antiviral Effect ◽  
Neutralization Assay ◽  
Drug Candidates ◽  
Main Protease ◽  
Human Coronaviruses ◽  
Calpain Inhibitors

AbstractAs the COVID-19 pandemic continues to fold out, the morbidity and mortality are increasing daily. Effective treatment for SARS-CoV-2 is urgently needed. We recently discovered four SARS-CoV-2 main protease (Mpro) inhibitors including boceprevir, calpain inhibitors II and XII and GC-376 with potent antiviral activity against infectious SARS-CoV-2 in cell culture. Despite the weaker enzymatic inhibition of calpain inhibitors II and XII against Mpro compared to GC-376, calpain inhibitors II and XII had more potent cellular antiviral activity. This observation promoted us to hypothesize that the cellular antiviral activity of calpain inhibitors II and XII might also involve the inhibition of cathepsin L in addition to Mpro. To test this hypothesis, we tested calpain inhibitors II and XII in the SARS-CoV-2 pseudovirus neutralization assay in Vero E6 cells and found that both compounds significantly decreased pseudoviral particle entry into cells, indicating their role in inhibiting cathepsin L. The involvement of cathepsin L was further confirmed in the drug time-of-addition experiment. In addition, we found that these four compounds not only inhibit SARS-CoV-2, but also SARS-CoV, MERS-CoV, as well as human coronaviruses (CoVs) 229E, OC43, and NL63. The mechanism of action is through targeting the viral Mpro, which was supported by the thermal shift binding assay and enzymatic FRET assay. We further showed that these four compounds have additive antiviral effect when combined with remdesivir. Altogether, these results suggest that boceprevir, calpain inhibitors II and XII, and GC-376 are not only promising antiviral drug candidates against existing human coronaviruses, but also might work against future emerging CoVs.

scholarly journals Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against Mpro and cathepsin L

2020 ◽  
Author(s):  
Michael Dominic Sacco ◽  
Chunlong Ma ◽  
Panagiotis Lagarias ◽  
Ang Gao ◽  
Julia Alma Townsend ◽  
...  
Keyword(s):  
Viral Entry ◽  
Cathepsin L ◽  
Antiviral Drug ◽  
Binding Mode ◽  
Calpain Inhibitor ◽  
Catalytic Core ◽  
Main Protease ◽  
Dual Inhibitors ◽  
Calpain Inhibitors

AbstractThe main protease (Mpro) of SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic, is a key antiviral drug target. While most SARS-CoV-2 Mpro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently discovered several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II/XII, which are also active against human cathepsin L, a host-protease that is important for viral entry. To determine the binding mode of these calpain inhibitors and establish a structure-activity relationship, we solved X-ray crystal structures of Mpro in complex with calpain inhibitors II and XII, and three analogues of GC-376, one of the most potent Mpro inhibitors in vitro. The structure of Mpro with calpain inhibitor II confirmed the S1 pocket of Mpro can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. Interestingly, the structure of calpain inhibitor XII revealed an unexpected, inverted binding pose where the P1’ pyridine inserts in the S1 pocket and the P1 norvaline is positioned in the S1’ pocket. The overall conformation is semi-helical, wrapping around the catalytic core, in contrast to the extended conformation of other peptidomimetic inhibitors. Additionally, the structures of three GC-376 analogues UAWJ246, UAWJ247, and UAWJ248 provide insight to the sidechain preference of the S1’, S2, S3 and S4 pockets, and the superior cell-based activity of the aldehyde warhead compared with the α-ketoamide. Taken together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of Mpro inhibitors as SARS-CoV-2 antivirals.

scholarly journals Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L

2020 ◽  
Vol 6 (50) ◽  
pp. eabe0751 ◽  
Author(s):  
Michael Dominic Sacco ◽  
Chunlong Ma ◽  
Panagiotis Lagarias ◽  
Ang Gao ◽  
Julia Alma Townsend ◽  
...  
Keyword(s):  
Viral Entry ◽  
Cathepsin L ◽  
Antiviral Drug ◽  
Side Chain ◽  
Calpain Inhibitor ◽  
Main Protease ◽  
New Directions ◽  
Dual Inhibitors ◽  
Hydrophilic Residue ◽  
Calpain Inhibitors

The main protease (Mpro) of SARS-CoV-2 is a key antiviral drug target. While most Mpro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently found that several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II and XII, which are also active against human cathepsin L, a host protease that is important for viral entry. In this study, we solved x-ray crystal structures of Mpro in complex with calpain inhibitors II and XII and three analogs of GC-376. The structure of Mpro with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.

scholarly journals Repurposing Nucleoside Analogs for Human Coronaviruses

2020 ◽  
Vol 65 (1) ◽  
pp. e01652-20
Author(s):  
Keivan Zandi ◽  
Franck Amblard ◽  
Katie Musall ◽  
Jessica Downs-Bowen ◽  
Ruby Kleinbard ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antiviral Activity ◽  
Rna Polymerase ◽  
Nucleoside Analogs ◽  
Antiviral Effect ◽  
Serious Illness ◽  
Human Coronaviruses

ABSTRACTCoronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed confirmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. Of significance, sofosbuvir demonstrated no antiviral effect against CoV-2, and its triphosphate did not inhibit CoV-2 RNA polymerase.

scholarly journals Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1331-1335 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
X Ray ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Key Enzyme ◽  
Low Toxicity ◽  
Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

scholarly journals Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Antiviral Drug ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
A Cell ◽  
Aldehyde Groups ◽  
Clinical Potential

ABSTRACTSARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 μM and 0.04 μM respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 μM and 0.33 μM, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.

scholarly journals Elucidation on the Physicochemical Properties of Potential and Clinically Approved Antiviral Drugs: A Search for Effective Therapies against SARS-CoV-2 Infection

2020 ◽  
Vol 14 (suppl 1) ◽  
pp. 1025-1034
Author(s):  
Derick Erl P. Sumalapao
Keyword(s):  
Antiviral Activity ◽  
Physicochemical Properties ◽  
Vaccine Development ◽  
Heavy Atom ◽  
Antiviral Drug ◽  
Principal Component ◽  
Antiviral Drugs ◽  
Medical Emergency ◽  
Drug Candidates ◽  
Additional Information

COVID-19 has been confirmed in millions of individuals worldwide, rendering it a global medical emergency. In the absence of vaccines and the unavailability of effective drugs for the SARS-CoV-2 infection, vaccine development is being continuously explored and several antiviral compounds and immunotherapies are currently being investigated. Given the high similarity in genetic identity between SARS-CoV and SARS-CoV-2, the present investigation identified the interaction between the physicochemical properties and the antiviral activity of different potential and clinically approved antiviral drugs against SARS-CoV using hierarchically weighted principal component analysis. Representative drugs from the classes of neuraminidase inhibitors, reverse transcriptase inhibitors, protease inhibitors, nucleoside analogues, and other compounds with potential antiviral activity were examined. The pharmacologic classification and the biological activity of the different antiviral drugs were described using indices, namely, rotatable bond count, molecular weight, heavy atom count, and molecular complexity (92.32% contribution rate). The physicochemical properties and inhibitory action against SARS-CoV-2 of lopinavir, chloroquine, ivermectin, and ciclesonide validated the adequacy of the current computational approach. The findings of the present study provide additional information, although further investigation is warranted to identify potential targets and establish exact mechanisms, in the emergent search and design of antiviral drug candidates and their subsequent synthesis as effective therapies for COVID-19.

scholarly journals Evaluation of Antiviral Activities of Curcumin Derivatives against HSV-1 in Vero Cell Line

2010 ◽  
Vol 5 (12) ◽  
pp. 1934578X1000501 ◽  
Author(s):  
Keivan Zandi ◽  
Elissa Ramedani ◽  
Khosro Mohammadi ◽  
Saeed Tajbakhsh ◽  
Iman Deilami ◽  
...  
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Vero Cell ◽  
Cell Line ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
In Vitro Study ◽  
Vero Cell Line ◽  
Hsv 1

Antiviral drug resistance is one of the most common problems in medicine, and, therefore, finding new antiviral agents, especially from natural resources, seems to be necessary. This study was designed to assay the antiviral activity of curcumin and its new derivatives like gallium-curcumin and Cu-curcumin on replication of HSV-1 in cell culture. The research was performed as an in vitro study in which the antiviral activity of different concentrations of three substances including curcumin, Gallium-curcumin and Cu-curcumin were tested on HSV-1. The cytotoxicity of the tested compounds was also evaluated on the Vero cell line. The CC50 values for curcumin, gallium-curcumin and Cu-curcumin were 484.2 μg/mL, 255.8 μg/mL and 326.6 μg/mL, respectively, and the respective IC50 values 33.0 μg/mL, 13.9 μg/mL and 23.1 μg/mL. The calculated SI values were 14.6, 18.4 and 14.1, respectively. The results showed that curcumin and its new derivatives have remarkable antiviral effects on HSV-1 in cell culture.

Antiviral Activity of CTC-8 against Herpes Simplex Virus (HSV-1) in Cell Culture: Evidence for a Selective Antiviral Effect via a Cellular Mechanism

2003 ◽  
Vol 14 (4) ◽  
pp. 217-223 ◽  
Author(s):  
Tim Fitzmaurice ◽  
David R Harper ◽  
Hugh J Field
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Therapeutic Potential ◽  
Antiviral Effect ◽  
Short Period ◽  
Assay Time ◽  
Prostaglandin A1 ◽  
Simplex Virus ◽  
Toxic Concentrations ◽  
Hsv 1

A synthetic programme produced a series of compounds related to natural prostaglandins, which are known to affect the growth of a number of viruses. Several of the compounds showed potent biological activity including antiviral effects. The compound CTC-8 [(S)-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-one] contains the cyclopentenone ring of prostaglandin A1, but the extended side chains common to the prostaglandin family are truncated. The present study demonstrates that CTC-8 inhibits HSV-1 replication in cell culture at sub-toxic concentrations. The antiviral effect was evidenced by reduction in infectious virus yield, although the compound was not effective in the standard plaque-reduction assay. Time-of-addition studies and other experiments provide a possible explanation for these results by suggesting that the antiviral activity is confined to a single cycle. Under the standard conditions of high-multiplicity infection in BHK cells it was notable that CTC-8 is most effective when added for a short period 6–8 h post-infection. Furthermore, multiple passage of HSV-1 in the presence of CTC-8 did not result in the selection of resistant mutants. The results of these and other experiments are consistent with the hypothesis that the mechanism by which CTC-8 inhibits virus replication involves a cellular target. These results encourage further research into the therapeutic potential of this series of compounds.

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