scholarly journals Identification of a Broad-Spectrum Viral Inhibitor Targeting a Novel Allosteric Site in the RNA-Dependent RNA Polymerases of Dengue Virus and Norovirus

2020 ◽  
Vol 11 ◽  
Author(s):  
Dongrong Yi ◽  
Quanjie Li ◽  
Lili Pang ◽  
Yujia Wang ◽  
Yongxin Zhang ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Broad Spectrum ◽  
Rna Polymerases ◽  
Allosteric Site ◽  
Viral Inhibitor

scholarly journals 25-Hydroxycholesterol-Conjugated EK1 Peptide with Potent and Broad-Spectrum Inhibitory Activity against SARS-CoV-2, Its Variants of Concern, and Other Human Coronaviruses

2021 ◽  
Vol 22 (21) ◽  
pp. 11869
Author(s):  
Qiaoshuai Lan ◽  
Chao Wang ◽  
Jie Zhou ◽  
Lijue Wang ◽  
Fanke Jiao ◽  
...  
Keyword(s):  
Public Health ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Fusion Inhibitor ◽  
Global Public Health ◽  
Newborn Mice ◽  
Viral Inhibitor ◽  
Modified Peptides ◽  
Human Coronaviruses ◽  
Enzymatic Product

The COVID-19 pandemic caused by SARS-CoV-2 infection poses a serious threat to global public health and the economy. The enzymatic product of cholesterol 25-hydroxylase (CH25H), 25-Hydroxycholesterol (25-HC), was reported to have potent anti-SARS-CoV-2 activity. Here, we found that the combination of 25-HC with EK1 peptide, a pan-coronavirus (CoV) fusion inhibitor, showed a synergistic antiviral activity. We then used the method of 25-HC modification to design and synthesize a series of 25-HC-modified peptides and found that a 25-HC-modified EK1 peptide (EK1P4HC) was highly effective against infections caused by SARS-CoV-2, its variants of concern (VOCs), and other human CoVs, such as HCoV-OC43 and HCoV-229E. EK1P4HC could protect newborn mice from lethal HCoV-OC43 infection, suggesting that conjugation of 25-HC with a peptide-based viral inhibitor was a feasible and universal strategy to improve its antiviral activity.

scholarly journals Labyrinthopeptins Exert Broad-Spectrum Antiviral Activity through Lipid-Binding-Mediated Virolysis

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Hans Prochnow ◽  
Katharina Rox ◽  
N. V. Suryanarayana Birudukota ◽  
Loreen Weichert ◽  
Sven-Kevin Hotop ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Host Cell ◽  
Broad Spectrum ◽  
Zika Virus ◽  
Kaposi's Sarcoma ◽  
Chikungunya Virus ◽  
Viral Infections ◽  
Kaposi’S Sarcoma ◽  
Membrane Lipid ◽  
Virus Zika

ABSTRACT To counteract the serious health threat posed by known and novel viral pathogens, drugs that target a variety of viruses through a common mechanism have attracted recent attention due to their potential in treating (re)emerging infections, for which direct-acting antivirals are not available. We found that labyrinthopeptins A1 and A2, the prototype congeners of carbacyclic lanthipeptides, inhibit the proliferation of diverse enveloped viruses, including dengue virus, Zika virus, West Nile virus, hepatitis C virus, chikungunya virus, Kaposi’s sarcoma-associated herpesvirus, cytomegalovirus, and herpes simplex virus, in the low micromolar to nanomolar range. Mechanistic studies on viral particles revealed that labyrinthopeptins induce a virolytic effect through binding to the viral membrane lipid phosphatidylethanolamine (PE). These effects are enhanced by a combined equimolar application of both labyrinthopeptins, and a clear synergism was observed across a concentration range corresponding to 10% to 90% inhibitory concentrations of the compounds. Time-resolved experiments with large unilamellar vesicles (LUVs) reveal that membrane lipid raft compositions (phosphatidylcholine [PC]/PE/cholesterol/sphingomyelin at 17:10:33:40) are particularly sensitive to labyrinthopeptins in comparison to PC/PE (90:10) LUVs, even though the overall PE amount remains constant. Labyrinthopeptins exhibited low cytotoxicity and had favorable pharmacokinetic properties in mice (half-life [t1/2] = 10.0 h), which designates them promising antiviral compounds acting by an unusual viral lipid targeting mechanism. IMPORTANCE For many viral infections, current treatment options are insufficient. Because the development of each antiviral drug is time-consuming and expensive, the prospect of finding broad-spectrum antivirals that can fight multiple, diverse viruses—well-known viruses as well as (re)emerging species—has gained attention, especially for the treatment of viral coinfections. While most known broad-spectrum agents address processes in the host cell, we found that targeting lipids of the free virus outside the host cell with the natural products labyrinthopeptin A1 and A2 is a viable strategy to inhibit the proliferation of a broad range of viruses from different families, including chikungunya virus, dengue virus, Zika virus, Kaposi’s sarcoma-associated herpesvirus, and cytomegalovirus. Labyrinthopeptins bind to viral phosphatidylethanolamine and induce virolysis without exerting cytotoxicity on host cells. This represents a novel and unusual mechanism to tackle medically relevant viral infections.

scholarly journals BIKE regulates dengue virus infection and is a cellular target for broad-spectrum antivirals

2020 ◽  
Vol 184 ◽  
pp. 104966
Author(s):  
Szuyuan Pu ◽  
Stanford Schor ◽  
Marwah Karim ◽  
Sirle Saul ◽  
Makeda Robinson ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Broad Spectrum ◽  
Dengue Virus Infection ◽  
Cellular Target

scholarly journals Induction of a Peptide with Activity against a Broad Spectrum of Pathogens in the Aedes aegypti Salivary Gland, following Infection with Dengue Virus

2011 ◽  
Vol 7 (1) ◽  
pp. e1001252 ◽  
Author(s):  
Natthanej Luplertlop ◽  
Pornapat Surasombatpattana ◽  
Sirilaksana Patramool ◽  
Emilie Dumas ◽  
Ladawan Wasinpiyamongkol ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Aedes Aegypti ◽  
Dengue Virus ◽  
Broad Spectrum

scholarly journals Designing a polytope for use in a broad-spectrum dengue virus vaccine

2018 ◽  
Vol 13 (2) ◽  
pp. 156-161
Author(s):  
Karimatul Himmah ◽  
Fitriyah ◽  
Tri Ardyati ◽  
Mufidah Afiyanti ◽  
Muhaimin Rifa'i ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Virus Vaccine ◽  
Broad Spectrum

scholarly journals Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257206
Author(s):  
R. V. Sriram Uday ◽  
Rajdip Misra ◽  
Annaram Harika ◽  
Sandip Dolui ◽  
Achintya Saha ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Active Site ◽  
Protein Conformation ◽  
Hydrophobic Interactions ◽  
Experimental Studies ◽  
Allosteric Site ◽  
Hydrogen Bond Formation ◽  
Computational Screening ◽  
Π Stacking ◽  
Ns3 Protease

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.

Development of a monoclonal antibody specific to envelope domain III with broad-spectrum detection of all four dengue virus serotypes

2016 ◽  
Vol 473 (4) ◽  
pp. 894-898 ◽  
Author(s):  
Sae-Hae Kim ◽  
Yu Na Kim ◽  
Thang Thua Truong ◽  
Nguyen Thi Thu Thuy ◽  
Le Quynh Mai ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Dengue Virus ◽  
Broad Spectrum ◽  
Spectrum Detection ◽  
Dengue Virus Serotypes ◽  
Domain Iii

Broad-spectrum catalytic metallopeptide inactivators of Zika and West Nile virus NS2B/NS3 proteases

2018 ◽  
Vol 54 (87) ◽  
pp. 12357-12360 ◽  
Author(s):  
Andrew M. Pinkham ◽  
Zhen Yu ◽  
J. A. Cowan
Keyword(s):  
West Nile Virus ◽  
Oxidative Damage ◽  
Dengue Virus ◽  
Broad Spectrum ◽  
West Nile ◽  
Viral Proteases ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

Catalytic metallopeptides promote irreversible oxidative damage to Flaviviridae viral proteases and offer the prospect of broad spectrum activity against Zika, West Nile, and Dengue virus with one drug.

Comparison of dengue virus and HCV: from impact on global health to their RNA-dependent RNA polymerases

2014 ◽  
Vol 9 (1) ◽  
pp. 53-67 ◽  
Author(s):  
Supanee Potisopon ◽  
Stéphane Priet ◽  
Barbara Selisko ◽  
Bruno Canard
Keyword(s):  
Global Health ◽  
Dengue Virus ◽  
Rna Polymerases
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