scholarly journals Structural and Virological Studies of the Stages of Virus Replication That Are Affected by Antirhinovirus Compounds

2004 ◽  
Vol 78 (20) ◽  
pp. 11061-11069 ◽  
Author(s):  
Ying Zhang ◽  
Alan A. Simpson ◽  
Rebecca M. Ledford ◽  
Carol M. Bator ◽  
Sugoto Chakravarty ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Virus Replication ◽  
Cell Attachment ◽  
Antiviral Effect ◽  
Binding Pocket ◽  
Drug Binding ◽  
Binding Studies ◽  
Hydrophobic Pocket ◽  
Viral Protein 1 ◽  
Inhibition Studies

ABSTRACT Pleconaril is a broad-spectrum antirhinovirus and antienterovirus compound that binds into a hydrophobic pocket within viral protein 1, stabilizing the capsid and resulting in the inhibition of cell attachment and RNA uncoating. When crystals of human rhinovirus 16 (HRV16) and HRV14 are incubated with pleconaril, drug occupancy in the binding pocket is lower than when pleconaril is introduced during assembly prior to crystallization. This effect is far more marked in HRV16 than in HRV14 and is more marked with pleconaril than with other compounds. These observations are consistent with virus yield inhibition studies and radiolabeled drug binding studies showing that the antiviral effect of pleconaril against HRV16 is greater on the infectivity of progeny virions than the parent input viruses. These data suggest that drug integration into the binding pocket during assembly, or at some other late stage in virus replication, may contribute to the antiviral activity of capsid binding compounds.

scholarly journals EPSTI1 Is Involved in IL-28A-Mediated Inhibition of HCV Infection

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Xianghe Meng ◽  
Darong Yang ◽  
Rong Yu ◽  
Haizhen Zhu
Keyword(s):  
Life Cycle ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Virus Replication ◽  
Antiviral Effect ◽  
Vital Role ◽  
Hcv Infection ◽  
Rnase L ◽  
Interferon Treatment

It has been reported that IFN-λs inhibit HCV replication in vitro. But the mechanisms of how IL-28A conducts antiviral activity and the functions of IL-28A-induced ISGs (IFN-stimulated genes) are not fully understood. In this study, we found that IL-28A has the antiviral effect on HCV life cycle including viral replication, assembly, and release. IL-28A and IFN-αsynergistically inhibit virus replication. EPSTI1 (epithelial-stromal interaction 1), one of IL-28A-induced ISGs, plays a vital role in IL-28A-mediated antiviral activity. Furthermore, forced expression of EPSTI1 effectively inhibits HCV replication in the absence of interferon treatment, and knockdown of EPSTI1 contributes to viral enhancement. EPSTI1 can activate PKR promoter and induce several PKR-dependent genes, including IFN-β, IFIT1, OAS1, and RNase L, which is responsible for EPSTI1-mediated antiviral activity.

scholarly journals Modeling Borna Disease Virus In Vitro Spread Reveals the Mode of Antiviral Effect Conferred by an Endogenous Bornavirus-Like Element

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Kwang Su Kim ◽  
Yusuke Yamamoto ◽  
Shinji Nakaoka ◽  
Keizo Tomonaga ◽  
Shingo Iwami ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Disease Virus ◽  
Virus Replication ◽  
Ground Squirrel ◽  
Cultured Cells ◽  
Antiviral Effect ◽  
Endogenous Retroviruses ◽  
Virus Spread ◽  
Borna Disease

ABSTRACT Endogenous retroviruses have demonstrated exaptation during long-term evolution with hosts, e.g., resulting in acquisition of antiviral effect on related extant viral infections. While empirical studies have found that an endogenous bornavirus-like element derived from viral nucleoprotein (itEBLN) in the ground squirrel genome shows antiviral effect on virus replication and de novo infection, the antiviral mechanism, dynamics, and quantitative effect of itEBLN remain unknown. In this study, we experimentally and theoretically investigated the dynamics of how an extant bornavirus, Borna disease virus 1 (BoDV-1), spreads and replicates in uninfected, BoDV-1-infected, and itEBLN-expressing cultured cells. Quantifying antiviral effect based on time course data sets, we found that the antiviral effects of itEBLN are estimated to be 75% and 34% on intercellular virus spread and intracellular virus replication, respectively. This discrepancy between intercellular virus spread and intracellular viral replication suggests that viral processes other than the replication of viral ribonucleoprotein complex (RNP) contributed to the suppression of virus spread in itEBLN-expressing cells. Because itEBLN binds to the BoDV-1 RNP, the suppression of viral RNP trafficking can be an attractive candidate explaining this discrepancy. IMPORTANCE Accumulating evidence suggests that some endogenous viral elements (EVEs), including endogenous retroviruses and endogenous nonretroviral virus elements, have acquired functions in the host as a result of long-term coevolution. Recently, an endogenous bornavirus-like element (itEBLN) found in the ground squirrel genome has been shown to have antiviral activity against exogenous bornavirus infection. In this study, we first quantified bornavirus spread in cultured cells and then calculated the antiviral activity of itEBLN on bornavirus infection. The calculated antiviral activity of itEBLN suggests its suppression of multiple processes in the viral life cycle. To our knowledge, this is the first study quantifying the antiviral activity of EVEs and speculating on a model of how some EVEs have acquired antiviral activity during host-virus arms races.

scholarly journals Pocket Factors Are Unlikely To Play a Major Role in the Life Cycle of Human Rhinovirus

2007 ◽  
Vol 81 (12) ◽  
pp. 6307-6315 ◽  
Author(s):  
Umesh Katpally ◽  
Thomas J. Smith
Keyword(s):  
Life Cycle ◽  
Host Cell ◽  
Cell Attachment ◽  
Limited Proteolysis ◽  
Genetic Material ◽  
Binding Pocket ◽  
Drug Binding ◽  
Human Rhinovirus ◽  
Mouth Disease Virus ◽  
Binding Cavity

ABSTRACT Human rhinovirus 14 (HRV14) is a member of the rhinovirus genus, which belongs to the picornavirus family, which includes clinically and economically important members, such as poliovirus, foot-and-mouth disease virus, and endomyocarditis virus. Capsid stability plays an important role in the viral infection process, in that it needs to be stable enough to move from cell to cell and yet be able to release its genetic material upon the appropriate environmental cues from the host cell. It has been suggested that certain host cell molecules, “pocket factors,” bind to the WIN drug-binding cavity beneath the canyon floor and provide transient stability to a number of the picornaviruses. To directly test this hypothesis, HRV14 was mutated in (V1188M, C1199W, and V1188M/C1199W) and around (S1223G) the drug-binding pocket. Infectivity, limited proteolysis, and matrix-assisted laser desorption ionization analyses indicate that filling the drug-binding pocket with bulky side chains is not deleterious to the viral life cycle and lends some stabilization to the capsid. In contrast, studies with the S1223G mutant suggest that this mutation at least partially overcomes WIN drug-mediated inhibition of cell attachment and capsid breathing. Finally, HRV16, which is inherently more stable than HRV14 in a number of respects, was found to “breathe” only at 37°C and did not tolerate stabilizing mutations in the drug-binding cavity. These results suggest that it is the drug-binding cavity itself and not the putative pocket factor that is crucial for the capsid dynamics, which is, in turn, necessary for infection.

scholarly journals Structure and inhibition of EV-D68, a virus that causes respiratory illness in children

Science ◽  
2015 ◽  
Vol 347 (6217) ◽  
pp. 71-74 ◽  
Author(s):  
Yue Liu ◽  
Ju Sheng ◽  
Andrei Fokine ◽  
Geng Meng ◽  
Woong-Hee Shin ◽  
...  
Keyword(s):  
Respiratory Illness ◽  
Binding Pocket ◽  
The United States ◽  
Effective Concentration ◽  
Drug Binding ◽  
Drug Candidate ◽  
Hydrophobic Drug ◽  
Half Maximal Effective Concentration ◽  
Enterovirus D68 ◽  
Viral Protein 1

Enterovirus D68 (EV-D68) is a member ofPicornaviridaeand is a causative agent of recent outbreaks of respiratory illness in children in the United States. We report here the crystal structures of EV-D68 and its complex with pleconaril, a capsid-binding compound that had been developed as an anti-rhinovirus drug. The hydrophobic drug-binding pocket in viral protein 1 contained density that is consistent with a fatty acid of about 10 carbon atoms. This density could be displaced by pleconaril. We also showed that pleconaril inhibits EV-D68 at a half-maximal effective concentration of 430 nanomolar and might, therefore, be a possible drug candidate to alleviate EV-D68 outbreaks.

scholarly journals Comparative analysis of the molecular mechanism of resistance to vapendavir across a panel of picornavirus species

2020 ◽  
Author(s):  
Kristina Lanko ◽  
Liang Sun ◽  
Mathy Froeyen ◽  
Pieter Leyssen ◽  
Leen Delang ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Molecular Mechanism ◽  
Viral Particle ◽  
Binding Pocket ◽  
Drug Binding ◽  
Viral Capsid ◽  
Drug Resistant ◽  
Hydrophobic Pocket ◽  
Resistant Phenotype

AbstractVapendavir is a rhino/enterovirus inhibitor that targets a hydrophobic pocket in the viral capsid. Drug-resistant variants were selected in vitro. Mutations in the drug-binding pocket in VP1 (C199R/Y in hRV14; I194F in PV1; M252L and A156T in EV-D68), typical for this class of compounds, were identified. We also observed mutations that are located outside the pocket (K167E in EV-D68 and G149C in hRV2) and that contribute to the resistant phenotype. Remarkably, the G149C substitution made the replication of human rhinovirus 2 dependent on the presence of vapendavir. Our data suggest that vapendavir binding to the capsid of the dependent isolate may be required to stabilize the viral particle and to allow efficient dissemination of the virus. Our results demonstrate that vapendavir-resistant pheno- and genotypes of clinically relevant picornavirus species are more complex than generally believed.

scholarly journals A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jessica Knox ◽  
Nicolas Joly ◽  
Edmond M. Linossi ◽  
José A. Carmona-Negrón ◽  
Natalia Jura ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Developmental Delay ◽  
Small Molecule ◽  
Parasitic Nematode ◽  
Kinase Inhibitor ◽  
Binding Pocket ◽  
Drug Binding ◽  
Nematode Infection ◽  
Selective Inhibitors ◽  
C Elegans

AbstractOver one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.

scholarly journals Phytochemical Characterization of Olea europea Leaf Extracts and Assessment of Their Anti-Microbial and Anti-HSV-1 Activity

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1085
Author(s):  
Ichrak Ben-Amor ◽  
Maria Musarra-Pizzo ◽  
Antonella Smeriglio ◽  
Manuela D’Arrigo ◽  
Rosamaria Pennisi ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Biological Properties ◽  
Leaf Extracts ◽  
Gram Positive Bacteria ◽  
Entry Assay ◽  
Olea Europea ◽  
Hsv 1

Owing to the richness of bioactive compounds, Olea europea leaf extracts exhibit a range of health effects. The present research evaluated the antibacterial and antiviral effect of leaf extracts obtained from Olea europea L. var. sativa (OESA) and Olea europea var. sylvestris (OESY) from Tunisia. LC-DAD-ESI-MS analysis allowed the identification of different compounds that contributed to the observed biological properties. Both OESA and OESY were active against Gram-positive bacteria (MIC values between 7.81 and 15.61 μg/mL and between 15.61 and 31.25 μg/mL against Staphylococcus aureus ATCC 6538 for OESY and OESA, respectively). The antiviral activity against the herpes simplex type 1 (HSV-1) was assessed on Vero cells. The results of cell viability indicated that Olea europea leaf extracts were not toxic to cultured Vero cells. The half maximal cytotoxic concentration (CC50) values for OESA and OESY were 0.2 mg/mL and 0.82 mg/mL, respectively. Furthermore, both a plaque reduction assay and viral entry assay were used to demonstrate the antiviral activity. In conclusion, Olea europea leaf extracts demonstrated a bacteriostatic effect, as well as remarkable antiviral activity, which could provide an alternative treatment against resistant strains.

scholarly journals Characterization of the Acetate Binding Pocket in the Methanosarcina thermophila Acetate Kinase

2005 ◽  
Vol 187 (7) ◽  
pp. 2386-2394 ◽  
Author(s):  
Cheryl Ingram-Smith ◽  
Andrea Gorrell ◽  
Sarah H. Lawrence ◽  
Prabha Iyer ◽  
Kerry Smith ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Binding Pocket ◽  
Acetate Kinase ◽  
Phosphoryl Group ◽  
Acetyl Phosphate ◽  
Hydrophobic Pocket ◽  
Methanosarcina Thermophila ◽  
Methyl Group ◽  
Substrate Binding Sites

ABSTRACT Acetate kinase catalyzes the reversible magnesium-dependent synthesis of acetyl phosphate by transfer of the ATP γ-phosphoryl group to acetate. Inspection of the crystal structure of the Methanosarcina thermophila enzyme containing only ADP revealed a solvent-accessible hydrophobic pocket formed by residues Val93, Leu122, Phe179, and Pro232 in the active site cleft, which identified a potential acetate binding site. The hypothesis that this was a binding site was further supported by alignment of all acetate kinase sequences available from databases, which showed strict conservation of all four residues, and the recent crystal structure of the M. thermophila enzyme with acetate bound in this pocket. Replacement of each residue in the pocket produced variants with Km values for acetate that were 7- to 26-fold greater than that of the wild type, and perturbations of this binding pocket also altered the specificity for longer-chain carboxylic acids and acetyl phosphate. The kinetic analyses of variants combined with structural modeling indicated that the pocket has roles in binding the methyl group of acetate, influencing substrate specificity, and orienting the carboxyl group. The kinetic analyses also indicated that binding of acetyl phosphate is more dependent on interactions of the phosphate group with an unidentified residue than on interactions between the methyl group and the hydrophobic pocket. The analyses also indicated that Phe179 is essential for catalysis, possibly for domain closure. Alignments of acetate kinase, propionate kinase, and butyrate kinase sequences obtained from databases suggested that these enzymes have similar catalytic mechanisms and carboxylic acid substrate binding sites.

Evaluation of antiviral activity of piperazine against Chikungunya virus targeting hydrophobic pocket of alphavirus capsid protein

2017 ◽  
Vol 146 ◽  
pp. 102-111 ◽  
Author(s):  
Megha Aggarwal ◽  
Ramanjit Kaur ◽  
Amrita Saha ◽  
Rajat Mudgal ◽  
Ravi Yadav ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Capsid Protein ◽  
Chikungunya Virus ◽  
Hydrophobic Pocket

scholarly journals Structural basis for subtype-specific inhibition of the P2X7 receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Akira Karasawa ◽  
Toshimitsu Kawate
Keyword(s):  
P2x7 Receptor ◽  
Hydrophobic Interactions ◽  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Atp Binding ◽  
Allosteric Site ◽  
Channel Opening ◽  
A Site ◽  
Novel Drug

The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.

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