2019
DOI: 10.1016/j.antiviral.2019.02.008
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Identification of small molecule inhibitors targeting the Zika virus envelope protein

Abstract: The recent emergence of Zika virus, a mosquito-borne flavivirus, in the Americas has shed light on the severe neurological diseases associated with infection, notably congenital microcephaly in newborns and Guillain-Barré syndrome in adults. Despite the recent focus on Zika virus, there are currently no approved vaccines or antiviral therapies available to treat or prevent infection. In this study we established a competitive amplified luminescent proximity homogeneous assay (ALPHAscreen) to identify small mol… Show more

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Cited by 14 publications
(11 citation statements)
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References 29 publications
(33 reference statements)
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“…For example, serum concentration of imatinib mesylate ranges between 0.138 mg/ml and 2.816 mg/ml (median = 1.344 mg/ml) [50], which is higher than what we used for mosquito feeding (58.97 μg/ml); the patient serum level of MPA ranges from 0.45 to 6.5 mg/l (median = 2.1 mg/l) [51, 52], which is lower than that we fed mosquitoes on (32.04 μg/ml); the level of CsA in patient blood ranges from 212 to 1358 ng/ml [53], which is higher than that in blood meal can kill mosquitoes (120.26 ng/ml); the median concentration of Actinomycin D in patient plasma ranges from 24.4 to 128 μg/l between 5 and 15 min post administration [54], which is similar to that in blood meal can kill mosquitoes (125.5 ng/l). It is standard practice to use uniform concentrations when screening multiple compounds for bioactivity such as anti-viral action [17, 55]. Since we did not observe complete virus-blocking (infection intensity of zero) for any of the drugs, even at concentrations higher than patient serum levels, we did not pursue testing of lower concentrations.…”
Section: Discussionmentioning
confidence: 99%
“…For example, serum concentration of imatinib mesylate ranges between 0.138 mg/ml and 2.816 mg/ml (median = 1.344 mg/ml) [50], which is higher than what we used for mosquito feeding (58.97 μg/ml); the patient serum level of MPA ranges from 0.45 to 6.5 mg/l (median = 2.1 mg/l) [51, 52], which is lower than that we fed mosquitoes on (32.04 μg/ml); the level of CsA in patient blood ranges from 212 to 1358 ng/ml [53], which is higher than that in blood meal can kill mosquitoes (120.26 ng/ml); the median concentration of Actinomycin D in patient plasma ranges from 24.4 to 128 μg/l between 5 and 15 min post administration [54], which is similar to that in blood meal can kill mosquitoes (125.5 ng/l). It is standard practice to use uniform concentrations when screening multiple compounds for bioactivity such as anti-viral action [17, 55]. Since we did not observe complete virus-blocking (infection intensity of zero) for any of the drugs, even at concentrations higher than patient serum levels, we did not pursue testing of lower concentrations.…”
Section: Discussionmentioning
confidence: 99%
“…3,6 Several small-molecule inhibitors screened from chemical libraries have been reported to prevent the membrane fusion required for DENV, ZIKV, or other flavivirus infections. [7][8][9][10][11][12][13][14][15][16] Since the membrane fusion is required for DENV infection, several anti-fusion human monoclonal antibodies (mAbs) derived from patients with secondary infections but not primary infections were reported to present high-avidity and potent neutralization. 17,18 These high-avidity and potent neutralizing anti-fusion mAbs would be expected to be protective in vivo.…”
Section: Introductionmentioning
confidence: 99%
“…Thanks to similar lines of efforts, an AlphaScreen HTS based on the ZIKV E protein was carried on two commercially available libraries for a total of 26,954 compounds. [129] All compounds exhibiting promising IC 90 values ranging from 5.2 to 20.3 μM in the AlphaScreen were next evaluated for their antiviral activity (PRA on Vero cells). Among the most promising seven compounds, derivative 34 (Figure 9) exhibited the most potent anti-ZIKV activity (EC 90 = 5.1 μM) coupled with low toxicity (CC 50 = 98 μM).…”
Section: E Protein Inhibitorsmentioning
confidence: 99%