Recent Advances in Targeting Dengue and West Nile Virus Proteases Using Small Molecule Inhibitors

Steuber, H.; Kanitz, Manuel; Ehlert, F; Diederich, Wibke E.

doi:10.1007/7355_2014_46

Cited by 3 publications

(1 citation statement)

References 137 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The proteolytic activity of WNV and DENV is located in the N-terminal part of its NS3 protein, which is associated to the cytosolic site of the endoplasmatic reticulum via noncovalent interactions to a central hydrophilic domain of the integral membrane protein NS2B9. Due to the dependency of flavivirus replication on polyprotein processing, the viral protease emerged as a potential target for the treatment of flavivirus infections10 , 11. It is a typical serine protease containing a catalytic triad consisting of residues Ser135, His51, and Asp75.…”

Section: Introductionmentioning

confidence: 99%

Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication

Kouretova

Hammamy

Epp

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

West Nile virus (WNV) and Dengue virus (DENV) replication depends on the viral NS2B-NS3 protease and the host enzyme furin, which emerged as potential drug targets. Modification of our previously described WNV protease inhibitors by basic phenylalanine analogs provided compounds with reduced potency against the WNV and DENV protease. In a second series, their decarboxylated P1-trans-(4-guanidino)cyclohexylamide was replaced by an arginyl-amide moiety. Compound 4-(guanidinomethyl)-phenylacetyl-Lys-Lys-Arg-NH inhibits the NS2B-NS3 protease of WNV with an inhibition constant of 0.11 µM. Due to the similarity in substrate specificity, we have also tested the potency of our previously described multibasic furin inhibitors. Their further modification provided chimeric inhibitors with additional potency against the WNV and DENV proteases. A strong inhibition of WNV and DENV replication in cell culture was observed for the specific furin inhibitors, which reduced virus titers up to 10,000-fold. These studies reveal that potent inhibitors of furin can block the replication of DENV and WNV.

show abstract

Section: Introductionmentioning

confidence: 99%

Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication

Kouretova

Hammamy

Epp

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

Profiling of flaviviral NS2B-NS3 protease specificity provides a structural basis for the development of selective chemical tools that differentiate Dengue from Zika and West Nile viruses

Rut

Groborz

Zhang³

et al. 2020

Antiviral Research

View full text Add to dashboard Cite

In-silico screening for anti-Zika virus phytochemicals

Byler

Ogungbe

Setzer

2016

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

Zika virus (ZIKV) is an arbovirus that has infected hundreds of thousands of people and is a rapidly expanding epidemic across Central and South America. ZIKV infection has caused serious, albeit rare, complications including Guillain-Barré syndrome and congenital microcephaly. There are currently no vaccines or antiviral agents to treat or prevent ZIKV infection, but there are several ZIKV non-structural proteins that may serve as promising antiviral drug targets. In this work, we have carried out an in-silico search for potential anti-Zika viral agents from natural sources. We have generated ZIKV protease, methyltransferase, and RNA-dependent RNA polymerase using homology modeling techniques and we have carried out molecular docking analyses of our in-house virtual library of phytochemicals with these protein targets as well as with ZIKV helicase. Overall, 2263 plant-derived secondary metabolites have been docked. Of these, 43 compounds that have drug-like properties have exhibited remarkable docking profiles to one or more of the ZIKV protein targets, and several of these are found in relatively common herbal medicines, suggesting promise for natural and inexpensive antiviral therapy for this emerging tropical disease.

show abstract

Recent Advances in Targeting Dengue and West Nile Virus Proteases Using Small Molecule Inhibitors

Cited by 3 publications

References 137 publications

Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication

Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication

Profiling of flaviviral NS2B-NS3 protease specificity provides a structural basis for the development of selective chemical tools that differentiate Dengue from Zika and West Nile viruses

In-silico screening for anti-Zika virus phytochemicals

Contact Info

Product

Resources

About