Zika virus NS2B/NS3 proteinase: A new target for an old drug - Suramin a lead compound for NS2B/NS3 proteinase inhibition-

Coronado, Mônika A.; Eberle, Raphael J.; Bleffert, Nicole; Feuerstein, Sophie; Olivier, Danilo S.; Moraes, Fábio Rogério de; Willbold, Dieter; Arni, R.K.

doi:10.1016/j.antiviral.2018.10.019

Cited by 25 publications

(29 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Results of the Cp -CobM fluorescence quenching after ligand titration were used to determine the dissociation constant (K d ), a nonlinear saturation curve approach and a modified Hill equation (Supplementary Fig. S7) was combined 26 .…”

Section: Resultsmentioning

confidence: 99%

“…denitrificans SAM6.3 11 CbiL/CobI M . Thermautotrophicus SAM6.71 ± 0.8 26 SAM-dependent methyltransferases Adenine-N6 methyl- transferase B . subtilis SAM1.2 ± 0.3 27 Adenine-specific DNA methyltransferase T .…”

Section: Resultsmentioning

confidence: 99%

“…A combination of a nonlinear saturation curve approach and a modified Hill equation were used to determine the K d values, previously described in Coronado et al . 26 .…”

Section: Methodsmentioning

confidence: 99%

“…The general setup for the Cp- CobM homology simulations in native form and with ligands were performed with some modification as described in Coronado et al . 26 .…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Binding studies of a putative C. pseudotuberculosis target protein from Vitamin B12 Metabolism

Peinado

Olivier

Eberle

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Vitamin B 12 acts as a cofactor for various metabolic reactions important in living organisms. The Vitamin B 12 biosynthesis is restricted to prokaryotes, which means, all eukaryotic organisms must acquire this molecule through diet. This study presents the investigation of Vitamin B 12 metabolism and the characterization of precorrin-4 C(11)-methyltransferase (CobM), an enzyme involved in the biosynthesis of Vitamin B 12 in Corynebacterium pseudotuberculosis . The analysis of the C . pseudotuberculosis genome identified two Vitamin B 12 -dependent pathways, which can be strongly affected by a disrupted vitamin metabolism. Molecular dynamics, circular dichroism, and NMR-STD experiments identified regions in CobM that undergo conformational changes after s-adenosyl-L-methionine binding to promote the interaction of precorrin-4, a Vitamin B 12 precursor. The binding of s-adenosyl-L-methionine was examined along with the competitive binding of adenine, dATP, and suramin. Based on fluorescence spectroscopy experiments the dissociation constant for the four ligands and the target protein could be determined; SAM (1.4 ± 0.7 µM), adenine (17.8 ± 1.5 µM), dATP (15.8 ± 2.0 µM), and Suramin (6.3 ± 1.1 µM). The results provide rich information for future investigations of potential drug targets within the C . pseudotuberculosis’s Vitamin B12 metabolism and related pathways to reduce the pathogen’s virulence in its hosts.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…A combination of a nonlinear saturation curve approach and a modified Hill equation were used to determine the K d values, previously described in Coronado et al . 26 .…”

Section: Methodsmentioning

confidence: 99%

“…The general setup for the Cp- CobM homology simulations in native form and with ligands were performed with some modification as described in Coronado et al . 26 .…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Binding studies of a putative C. pseudotuberculosis target protein from Vitamin B12 Metabolism

Peinado

Olivier

Eberle

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additional natural flavonoids like myricitin, quercetin, luteolin, isorhamnetin, and apigerin, and the phenol curcumin inhibit the N2B-NS3 noncompetitively [130], although some of them seem to be promiscuous drugs, as it has been reported that they affect viral binding [130,131,132]. A similar case is suramin, an anti-parasitic, that inhibits NS2B/NS3 complex [133], but also viral binding to the cell membrane [131,132]. On the other hand, by screening a battery of almost 3000 approved and investigational drugs, three compounds (temoporfin, niclosamide, and nitazoxanide) were identified that presented inhibitory activity against ZIKV and also DENV, JEV, YFV, and WNV [134].…”

Section: Antiviralsmentioning

confidence: 99%

Therapeutic Advances Against ZIKV: A Quick Response, a Long Way to Go

Saiz

2019

Pharmaceuticals

View full text Add to dashboard Cite

Zika virus (ZIKV) is a mosquito-borne flavivirus that spread throughout the American continent in 2015 causing considerable worldwide social and health alarm due to its association with ocular lesions and microcephaly in newborns, and Guillain–Barré syndrome (GBS) cases in adults. Nowadays, no licensed vaccines or antivirals are available against ZIKV, and thus, in this very short time, the scientific community has conducted enormous efforts to develop vaccines and antivirals. So that, different platforms (purified inactivated and live attenuated viruses, DNA and RNA nucleic acid based candidates, virus-like particles, subunit elements, and recombinant viruses) have been evaluated as vaccine candidates. Overall, these vaccines have shown the induction of vigorous humoral and cellular responses, the decrease of viremia and viral RNA levels in natural target organs, the prevention of vertical and sexual transmission, as well as that of ZIKV-associated malformations, and the protection of experimental animal models. Some of these vaccine candidates have already been assayed in clinical trials. Likewise, the search for antivirals have also been the focus of recent investigations, with dozens of compounds tested in cell culture and a few in animal models. Both direct acting antivirals (DAAs), directed to viral structural proteins and enzymes, and host acting antivirals (HAAs), directed to cellular factors affecting all steps of the viral life cycle (binding, entry, fusion, transcription, translation, replication, maturation, and egress), have been evaluated. It is expected that this huge collaborative effort will produce affordable and effective therapeutic and prophylactic tools to combat ZIKV and other related still unknown or nowadays neglected flaviviruses. Here, a comprehensive overview of the advances made in the development of therapeutic measures against ZIKV and the questions that still have to be faced are summarized.

show abstract

NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

Nunes

Santos

Fonseca

et al. 2021

Journal of Medical Virology

View full text Add to dashboard Cite

Zika virus (ZIKV) infections are associated with severe neurological complications and are a global public health concern. There are no approved vaccines or antiviral drugs to inhibit ZIKV replication. NS2B-NS3 protease (NS2B-NS3 pro), which is essential for viral replication, is a promising molecular target for anti-ZIKV drugs. We conducted a systematic review to identify compounds with promising effects against ZIKV; we discussed their pharmacodynamic and pharmacophoric characteristics. The online search, performed using the PubMed/MEDLINE and SCOPUS databases, yielded 56 articles; seven relevant studies that reported nine promising compounds with inhibitory activity against ZIKV NS2B-NS3 pro were selected. Of these, five (niclosamide, nitazoxanide, bromocriptine, temoporfin, and novobiocin) are currently available on the market and have been tested for off-label use against ZIKV. The 50% inhibitory concentration values of these compounds for the inhibition of NS2B-NS3 pro ranged at 0.38-21.6 µM; most compounds exhibited noncompetitive inhibition (66%). All compounds that could inhibit the NS2B-NS3 pro complex showed potent in vitro anti-ZIKV activity with a 50% effective concentration ranging 0.024-50 µM. The 50% cytotoxic concentration of the compounds assayed using A549, Vero, and WRL-69 cell lines ranged at 0.6-1388.02 µM and the selectivity index was 3.07-1698. This review summarizes the most promising antiviral agents against ZIKV that have inhibitory activity against viral proteases.

show abstract

Zika virus NS2B/NS3 proteinase: A new target for an old drug - Suramin a lead compound for NS2B/NS3 proteinase inhibition-

Cited by 25 publications

References 43 publications

Binding studies of a putative C. pseudotuberculosis target protein from Vitamin B12 Metabolism

Binding studies of a putative C. pseudotuberculosis target protein from Vitamin B12 Metabolism

Therapeutic Advances Against ZIKV: A Quick Response, a Long Way to Go

NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

Contact Info

Product

Resources

About