Discovery and SAR studies of methionine–proline anilides as dengue virus NS2B-NS3 protease inhibitors

Zhou, Guo‐Chun; Weng, Zhibing; Shao, Xin; Liu, Fang; Nie, Xin; Liu, Jinsong; Wang, Decai; Wang, Chunguang; Guo, Kai

doi:10.1016/j.bmcl.2013.10.071

Cited by 31 publications

(20 citation statements)

References 17 publications

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“…The positive control, suramin, had an IC 50 value of 2.5 mg/mL (Table 1). Proline derivatives have been reported to possess antifungal, antiangiotensin-converting enzyme (ACE) (Morais et al, 2013) and antiviral (Zhou et al, 2013) activities. It has been reported that methionineproline anilides can inhibit the protease enzyme of dengue virus NS2B-NS3 (Zhou et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…Proline derivatives have been reported to possess antifungal, antiangiotensin-converting enzyme (ACE) (Morais et al, 2013) and antiviral (Zhou et al, 2013) activities. It has been reported that methionineproline anilides can inhibit the protease enzyme of dengue virus NS2B-NS3 (Zhou et al, 2013). Regarding the activity of A. andamanica leaves, it is reported that the leaves from this plant exhibited marked antiallergic and antiinflammatory effects using RBL-2H3 and RAW264.7 cells, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The leaves have been used for treatment of headache (Mabberley et al, 1995). Some of benzofuran derivatives from Aglaia genus show interesting biological activities including antiviral (Joshi et al, 1987;Zhou et al, 2013), antileukemic (Hayashi et al, 1982), and insecticidal activities (Ishibashi et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Anti-HIV-1 integrase effect of compounds fromAglaia andamanicaleaves and molecular docking study with acute toxicity test in mice

Puripattanavong

Tungcharoen

Chaniad

et al. 2015

Pharmaceutical Biology

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Anti-HIV-1 integrase effect of compounds fromAglaia andamanicaleaves and molecular docking study with acute toxicity test in mice

Puripattanavong

Tungcharoen

Chaniad

et al. 2015

Pharmaceutical Biology

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“…Table 2. ; B. one of the anilide reported by Zhou et al (56). Average hydrogen bond distance (Å) and % occupancy of interacting active site residues with NFV during simulation time.…”

Section: Conflict Of Interestsmentioning

confidence: 97%

Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus

et al. 2015

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Drug repurposing or re-profiling has become an effective strategy to identify novel indications for already-approved drugs. In this study, peptidomimetic FDA-approved HIV/HCV inhibitors were explored for their potential to be repurposed for the inhibition of the replication of dengue (DENV) and chikungunya virus (CHIKV) by targeting the NS2B-NS3 and NSP2 protease, respectively. MM/GBSA-based binding free energy results put nelfinavir forward as potential inhibitor of both dengue and chikungunya virus, which subsequently was further explored in a virus-cell-based assay for both viruses. Nelfinavir showed modest antiviral activity against CHIKV (EC 50 = 14 ± 1 µM and a selectivity index of 1.6) and was slightly more active against DENV-2 (EC 50 = 3.5 ± 0.4 µM and a selectivity index of 4.6). Even though the antiviral potency was limited, the fact that some activity was observed in these assays made it worth to explore the potential and properties of nelfinavir as a step-stone compound: a more detailed computational analysis was performed to understand the binding mode, interaction, hydrogen bond distance, occupancy and minimum pharmacophoric features. The comprehensive data set that resulted from these analyses may prove to be useful for the development of novel DENV and CHIKV protease inhibitors.

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“…The NS2B/NS3 protease is a particularly promising flavivirus therapeutic target, with extensive research on development of inhibitors as therapeutic candidates. Various strategies for Dengue NS2B/NS3 inhibitor development were recently reviewed (Luo et al, 2015), including design of both peptidic (Prusis et al, 2013; Xu et al, 2012) and non-peptidic small molecule inhibitors (Cabarcas-Montalvo et al, 2016; Chu et al, 2015; Deng et al, 2012; Lai et al, 2013a; Lai et al, 2013b; Li et al, 2015; Liu et al, 2014; Tomlinson and Watowich, 2011; Viswanathan et al, 2014; Wu et al, 2015; Zhou et al, 2013). There are already indications that resistance against protease inhibitors develops readily (Yang et al, 2011; Yang et al, 2014), consistent with the HCV protease inhibitor experience (Romano et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus

Lee¹,

et al. 2017

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Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain–Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activity (IC50) and binding affinity (KD) of ∼5-10 μM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a Ki value of 9.5 μM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a “pre-open conformation”, a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.

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Discovery and SAR studies of methionine–proline anilides as dengue virus NS2B-NS3 protease inhibitors

Cited by 31 publications

References 17 publications

Anti-HIV-1 integrase effect of compounds fromAglaia andamanicaleaves and molecular docking study with acute toxicity test in mice

Anti-HIV-1 integrase effect of compounds fromAglaia andamanicaleaves and molecular docking study with acute toxicity test in mice

Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus

Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus

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