scholarly journals A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

2021 ◽  
Vol 23 (1) ◽  
pp. 259
Author(s):  
Guillem Macip ◽  
Pol Garcia-Segura ◽  
Júlia Mestres-Truyol ◽  
Bryan Saldivar-Espinoza ◽  
Gerard Pujadas ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Inhibitory Concentration ◽  
Chemical Space ◽  
Effective Concentration ◽  
Inhibitory Potency ◽  
Main Protease ◽  
Ic50 Value ◽  
Covalent Inhibitors ◽  
Half Maximal Effective Concentration

In this review, we collected 1765 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro inhibitors from the bibliography and other sources, such as the COVID Moonshot project and the ChEMBL database. This set of inhibitors includes only those compounds whose inhibitory capacity, mainly expressed as the half-maximal inhibitory concentration (IC50) value, against M-pro from SARS-CoV-2 has been determined. Several covalent warheads are used to treat covalent and non-covalent inhibitors separately. Chemical space, the variation of the IC50 inhibitory activity when measured by different methods or laboratories, and the influence of 1,4-dithiothreitol (DTT) are discussed. When available, we have collected the values of inhibition of viral replication measured with a cellular antiviral assay and expressed as half maximal effective concentration (EC50) values, and their possible relationship to inhibitory potency against M-pro is analyzed. Finally, the most potent covalent and non-covalent inhibitors that simultaneously inhibit the SARS-CoV-2 M-pro and the virus replication in vitro are discussed.

scholarly journals Screening and Application of Chitin Synthase Inhibitors

Processes ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 1029
Author(s):  
Xiaozai Shi ◽  
Shuo Qiu ◽  
Yingling Bao ◽  
Hanchi Chen ◽  
Yuele Lu ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Inhibitory Concentration ◽  
Inhibitory Effect ◽  
Chitin Synthase ◽  
Fungal Cell ◽  
Ic50 Value ◽  
Further Development ◽  
Fungicide Target ◽  
Better Than

Chitin is an important part of the fungal cell wall, but is not found in plants and mammals, so chitin synthase (CHS) can be a green fungicide target. In this paper, 35 maleimide compounds were designed and synthesized as CHS inhibitors. All the screened compounds showed different degrees of CHS inhibitory activity and antifungal activity in vitro. In particular, the half–inhibitory concentration (IC50) value of compound 20 on CHS was 0.12 mM, and the inhibitory effect was better than that of the control polyoxin B (IC50 = 0.19 mM). At the same time, this compound also showed good antifungal activity and has further development value.

scholarly journals Nelfinavir Is Active Against SARS-CoV-2 in Vero E6 Cells

2020 ◽  
Author(s):  
Zhijian Xu ◽  
Hangping Yao ◽  
Jingshan Shen ◽  
Nanping Wu ◽  
Yechun Xu ◽  
...  
Keyword(s):  
Cellular Level ◽  
Effective Concentration ◽  
High Potency ◽  
Response Curves ◽  
Main Protease ◽  
Similar Dose ◽  
Nelfinavir Mesylate ◽  
Half Maximal Effective Concentration ◽  
Computational Drug Discovery ◽  
Target Agent

Utilizing an integrative computational drug discovery approach, we predicted that nelfinavir is a potential inhibitor of SARS-CoV-2 main protease. Further docking nelfinavir to 30 potential target proteins of COVID-19, we found that nelfinavir is most probably a multi-target agent. The half-maximal effective concentration (EC<sub>50</sub>) of nelfinavir mesylate against SARS-CoV-2 was 2.89±0.65 μM while that of remdesivir was 1.00±0.34 μM, both drugs showed similar dose-response curves. Based on its high potency against SARS-CoV-2 at cellular level, its higher exposure in lung than in plasma, its good safe profile and its potential to reduce inflammation, nelfinavir deserves further exploration for the treatment of COVID-19.

scholarly journals Strong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N4-Hydroxy- and 5-Methyl-β-l-Deoxycytidine Analogues

2007 ◽  
Vol 51 (7) ◽  
pp. 2523-2530 ◽  
Author(s):  
E. Matthes ◽  
A. Funk ◽  
I. Krahn ◽  
K. Gaertner ◽  
M. von Janta-Lipinski ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Inhibitory Concentration ◽  
Hbv Dna ◽  
Selective Inhibitor ◽  
Effective Concentration ◽  
Active Inhibitor ◽  
Hbv Replication ◽  
B Virus

ABSTRACT Novel N4-hydroxy- and 5-methyl-modified β-l-deoxycytidine analogues were synthesized and evaluated as anti-hepatitis B virus (HBV) agents. Their in vitro efficiencies were investigated in HepG2.2.15 cells stably transfected with HBV. β-l-2′,3′-Didehydro-2′,3′-dideoxy-N4-hydroxycytidine (β-l-Hyd4C) was most effective in reducing secreted HBV DNA (50% effective concentration [EC50], 0.03 μM), followed by β-l-2′,3′-dideoxy-3′-thia-N4-hydroxycytidine (EC50, 0.51 μM), β-l-2′,3′-dideoxy-N4-hydroxycytidine (EC50, 0.55 μM), and β-l-5-methyl-2′-deoxycytidine (EC50, 0.9 μM). The inhibition of the presumed target, the HBV DNA polymerase, by the triphosphates of some of the β-l-cytidine derivatives was also assessed. In accordance with the cell culture data, β-l-Hyd4C triphosphate was the most active inhibitor, with a 50% inhibitory concentration of 0.21 μM. The cytotoxicities of some of the 4-NHOH-modified β-l-nucleosides were dramatically lower than those of the corresponding cytidine analogues with the unmodified 4-NH2 group. The 50% cytotoxic concentrations for β-l-Hyd4C in HepG2 and HL-60 cells were 2,500 μM and 3,500 μM, respectively. In summary, our results demonstrate that at least β-l-Hyd4C can be recommended as a highly efficient and extremely selective inhibitor of HBV replication for further investigations.

scholarly journals In VitroEfficacy of Brincidofovir against Variola Virus

2014 ◽  
Vol 58 (9) ◽  
pp. 5570-5571 ◽  
Author(s):  
Victoria A. Olson ◽  
Scott K. Smith ◽  
Scott Foster ◽  
Yu Li ◽  
E. Randall Lanier ◽  
...  
Keyword(s):  
Animal Models ◽  
Effective Concentration ◽  
Variola Virus ◽  
Half Maximal Effective Concentration ◽  
Animal Rule ◽  
Virus Strains ◽  
Lipid Conjugate

ABSTRACTBrincidofovir (CMX001), a lipid conjugate of the acyclic nucleotide phosphonate cidofovir, is under development for smallpox treatment using “the Animal Rule,” established by the FDA in 2002. Brincidofovir reduces mortality caused by orthopoxvirus infection in animal models. Compared to cidofovir, brincidofovir has increased potency, is administered orally, and shows no evidence of nephrotoxicity. Here we report that the brincidofovir half-maximal effective concentration (EC50) against five variola virus strainsin vitroaveraged 0.11 μM and that brincidofovir was therefore nearly 100-fold more potent than cidofovir.

scholarly journals EVALUATION OF IN VITRO HEPATIC TOXICITY OF LEAVES OF PTEROSPERMUM ACERIFOLIUM (L.) WILLD.

2020 ◽  
pp. 118-120
Author(s):  
RANA DATTA ◽  
SANKHADIP BOSE ◽  
SUDIP KUMAR MANDAL
Keyword(s):  
Inhibitory Concentration ◽  
Methanolic Extract ◽  
In Vitro Cytotoxicity ◽  
Hepatic Toxicity ◽  
Hepatic Cells ◽  
Diphenyltetrazolium Bromide ◽  
Ic50 Value ◽  
Hepg2 Cell Lines ◽  
Dose Dependent

Objective: The objective of the study was to determine the in vitro hepatic toxicity profile of methanolic extract of leaves of Pterospermum acerifolium (L.) Willd. (MEPA) using a mammalian hepatic cell line (HepG2). Methods: To assess its in vitro hepatic toxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-2,5-diphenyltetrazolium bromide assay using MEPA at a concentration of 25 μg, 50 μg, 100 μg, 200 μg, and 300 μg was carried out. Sorafenib tosylate was used as the standard agent to assess cytotoxicity. Results: The inhibitory concentration 50 (IC50) value for HepG2 cell lines was determined after 24 h. Thereafter the cytotoxicity study was again performed with the ½ IC50, IC50, and 2IC50 doses of MEPA. Experimentally, the IC50 was found to be 150.42 μg/ml for HepG2 using MEPA. A dose-dependent cytotoxicity and reduction in optical density were also observed with incremental MEPA administration. Conclusion: The cytotoxic potential of MEPA was found to be much less than that of sorafenib tosylate. Thus, MEPA shows in vitro cytotoxicity in mammalian hepatic cells (HepG2) at a concentration as low as 100 μg.

scholarly journals Nelfinavir Is Active Against SARS-CoV-2 in Vero E6 Cells

2020 ◽  
Author(s):  
Zhijian Xu ◽  
Hangping Yao ◽  
Jingshan Shen ◽  
Nanping Wu ◽  
Yechun Xu ◽  
...  
Keyword(s):  
Cellular Level ◽  
Effective Concentration ◽  
High Potency ◽  
Response Curves ◽  
Main Protease ◽  
Similar Dose ◽  
Nelfinavir Mesylate ◽  
Half Maximal Effective Concentration ◽  
Computational Drug Discovery ◽  
Target Agent

Utilizing an integrative computational drug discovery approach, we predicted that nelfinavir is a potential inhibitor of SARS-CoV-2 main protease. Further docking nelfinavir to 30 potential target proteins of COVID-19, we found that nelfinavir is most probably a multi-target agent. The half-maximal effective concentration (EC<sub>50</sub>) of nelfinavir mesylate against SARS-CoV-2 was 2.89±0.65 μM while that of remdesivir was 1.00±0.34 μM, both drugs showed similar dose-response curves. Based on its high potency against SARS-CoV-2 at cellular level, its higher exposure in lung than in plasma, its good safe profile and its potential to reduce inflammation, nelfinavir deserves further exploration for the treatment of COVID-19.

scholarly journals Amnestic Concentrations of Etomidate Modulate GABAA,slowSynaptic Inhibition in Hippocampus

2009 ◽  
Vol 111 (4) ◽  
pp. 766-773 ◽  
Author(s):  
Shuiping Dai ◽  
Misha Perouansky ◽  
Robert A. Pearce
Keyword(s):  
Time Constant ◽  
Hippocampal Slices ◽  
Effective Concentration ◽  
Detectable Effect ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Phasic Inhibition ◽  
Half Maximal Effective Concentration

Background Gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition in the central nervous system exists in two forms: phasic (inhibitory postsynaptic currents, IPSCs) and tonic (nonsynaptic). Phasic inhibition is further subdivided into fast (GABA(A,fast)) and slow (GABA(A,slow)) IPSCs. By virtue of its dendritic location and kinetics, GABA(A,slow) has been proposed to control synaptic plasticity and memory. Etomidate is a nonbarbiturate, intravenous anesthetic that selectively modulates GABA(A) receptors and produces amnesia at low doses in vivo. This study tested whether correspondingly low concentrations of etomidate in vitro alter GABA(A,fast) and GABA(A,slow) phasic inhibition. Methods Electrophysiological recordings were obtained from hippocampal slices prepared from postnatal day 3-8 mice and maintained in organotypic culture for 10-14 days. Etomidate was applied at concentrations corresponding to one-half to four times the half maximal effective concentration that impairs hippocampus-dependent learning and memory--i.e., 0.125-1.0 microm. Results Etomidate 0.25 microm (the half maximal effective concentration) doubled the time constant of decay of GABA(A,slow) IPSCs, but it had no detectable effect on GABA(A,fast) IPSCs. Higher concentrations of etomidate had stronger effects on both types of phasic inhibition: 0.5 and 1 microm etomidate prolonged the time constant of decay by 310% and 410% for GABA(A,slow) and by 25% and 78% for GABA(A,fast). Concentrations of etomidate up to 1 microm had no significant effects on the amplitudes of either GABA(A,fast) or GABA(A,slow) IPSCs. Conclusions At concentrations that impair hippocampus-dependent memory, etomidate modulates GABA(A,slow) more strongly than GABA(A,fast) IPSCs. Effects of etomidate on GABA(A,slow) IPSCs may contribute to etomidate-induced amnesia.

scholarly journals In vitro anti-motility and antispasmodic effects of Garcinia mangostana extracts in isolated chicken ileum preparation

2019 ◽  
Vol 10 (2) ◽  
pp. 1444-1447
Author(s):  
Michelle Ooi Yi Ching ◽  
Sasikala Chinnappan ◽  
Mogana Sundari Rajagopal
Keyword(s):  
Effective Concentration ◽  
Aqueous Extracts ◽  
Inhibitory Effects ◽  
Garcinia Mangostana ◽  
Response Curves ◽  
Half Maximal Effective Concentration ◽  
Set Up ◽  
Smooth Muscle Contractions ◽  
Significant Concentration

Garcinia mangostana pericarps have been traditionally used in Southeast Asia for a variety of medicinal conditions. The present study was carried out to determine the anti-motility and antispasmodic effects of methanolic and aqueous G. mangostana extracts (MEM and AEM) on isolated chicken ileum. Extracts were prepared from the pericarp of G. mangostana using maceration technique with methanol and distilled water. Isolated ileum preparations were set up for recording in Tyrode’s solution at 37°C. Dose-response curves were plotted using various doses of agonist as control such as acetylcholine (ACh) and histamine. Atropine, mepyramine and extracts were used as an antagonist. The results showed that methanolic and aqueous extracts possess significant concentration-dependent inhibitory effects (p<0.05) on agonist-induced contractions. The half maximal effective concentration (EC50) of extracts and standard antagonists were higher than the agonist alone. Both methanolic and aqueous extract of G. mangostana exerts anti-motility and antispasmodic effects on smooth muscle contractions. The study provides findings that support G. mangostana can be the potential treatment for diarrhoea and spasm.

scholarly journals Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors

2020 ◽  
Author(s):  
Jerzy Osipiuk ◽  
Saara-Anne Azizi ◽  
Steve Dvorkin ◽  
Michael Endres ◽  
Robert Jedrzejczak ◽  
...  
Keyword(s):  
Peptidase Activity ◽  
Wild Type ◽  
Clinical Value ◽  
Structure Based Drug Design ◽  
Replication Studies ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Viral Proliferation ◽  
Mutant Forms

ABSTRACTThe number of new cases world-wide for the COVID-19 disease is increasing dramatically, while efforts to contain Severe Acute Respiratory Syndrome Coronavirus 2 is producing varied results in different countries. There are three key SARS-CoV-2 enzymes potentially targetable with antivirals: papain-like protease (PLpro), main protease (Mpro), and RNA-dependent RNA polymerase. Of these, PLpro is an especially attractive target because it plays an essential role in several viral replication processes, including cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex (RTC), and disruption of host viral response machinery to facilitate viral proliferation and replication. Moreover, this enzyme is conserved across different coronaviruses and promising inhibitors have already been discovered for its SARS-CoV variant. Here we report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the enzyme from SARS-CoV-2 in both wild-type and mutant forms. These efforts include the first structures of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors, determined at 1.60–2.70 Angstroms. This collection of structures provides fundamental molecular and mechanistic insight to PLpro, and critically, illustrates details for inhibitors recognition and interactions. All presented compounds inhibit the peptidase activity of PLpro in vitro, and some molecules block SARS-CoV-2 replication in cell culture assays. These collated findings will accelerate further structure-based drug design efforts targeting PLpro, with the ultimate goal of identifying high-affinity inhibitors of clinical value for SARS-CoV-2.

scholarly journals Short Communication:In VitroEfficacy Testing of Praziquantel, Ivermectin, and Oxfendazole againstTaenia SoliumCysts

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
S. Cederberg ◽  
C. S. Sikasunge ◽  
Å. Andersson ◽  
M. V. Johansen
Keyword(s):  
Culture Media ◽  
Taenia Solium ◽  
Effective Concentration ◽  
Effect Measurement ◽  
Recommended Dose ◽  
Drug Of Choice ◽  
Porcine Cysticercosis ◽  
Half Maximal Effective Concentration ◽  
Brain Cysts

Oxfendazole is recommended as the drug of choice for treating porcine cysticercosis. The drug does not kill brain cysts and is not registered for use in pigs. Latest its safety in the recommended dose has been questioned. The aim of this study was to investigate two alternative anthelminthics. The efficacy of praziquantel and ivermectin was compared to oxfendazoleIn VitroonTaenia solium. Cysts ofT. soliumwere isolated from infected pork and incubated in culture media together with the drugs. The degree of evagination was used as effect measurement and determined after 6 hours. Praziquantel had a half maximal effective concentration (EC50) of value 0.006 ± 0.001 μg/mL. Ivermectin did not show any impact on the evagination in concentrations from 0.001 to 30 μg/mL and neither did oxfendazole in concentrations from 0.001 to 50 μg/mL.

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