Synthesis and disulfide bond connectivity–activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B–NS3 protease

Gao, Yaojun; Cui, Tingru; Lam, Yulin

doi:10.1016/j.bmc.2009.12.026

Cited by 49 publications

(33 citation statements)

References 39 publications

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“…For example, aprotinin, a 58 amino acid protein, showed the highest inhibitory effect against the dengue protease at picomolar levels compared to the other standard serine protease inhibitors [33]. The peptidic α-keto amide [30] and cyclopeptide inhibitors [34] showed significant inhibition against dengue NS2B-NS3pro at micromolar dose ranges compared to the other peptidic inhibitors. In addition, the non-substrate based inhibitors, such as small molecule inhibitors, showed significant inhibitory activities at low micromolar concentrations against the flavivirus proteases [31,32].…”

Section: Discussionmentioning

confidence: 99%

Identification of natural antimicrobial agents to treat dengue infection: In vitro analysis of latarcin peptide activity against dengue virus

et al. 2014

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BackgroundAlthough there have been considerable advances in the study of dengue virus, no vaccines or anti-dengue drugs are currently available for humans. Therefore, new approaches are necessary for the development of potent anti-dengue drugs. Natural antimicrobial peptides (AMPs) with potent antiviral activities are potential hits-to-leads for antiviral drug discovery. We performed this study to identify and characterise the inhibitory potential of the latarcin peptide (Ltc 1, SMWSGMWRRKLKKLRNALKKKLKGE) against dengue virus replication in infected cells.ResultsThe Ltc 1 peptide showed a significantly inhibitory effect against the dengue protease NS2B-NS3pro at 37°C, a physiological human temperature, (IC50, 12.68 ± 3.2 μM), and greater inhibitory effect was observed at 40°C, a temperature similar to a high fever (IC50, 6.58 ± 4.1 μM). A greater reduction in viral load (p.f.u./ml) was observed at simultaneous (0.7 ± 0.3 vs. 7.2 ± 0.5 control) and post-treatment (1.8 ± 0.7 vs. 6.8 ± 0.6 control) compared to the pre-treatment (4.5 ± 0.6 vs. 6.9 ± 0.5 control). Treatment with the Ltc 1 peptide reduced the viral RNA in a dose-dependent manner with EC50 values of 8.3 ± 1.2, 7.6 ± 2.7 and 6.8 ± 2.5 μM at 24, 48 and 72 h, respectively.ConclusionsThe Ltc 1 peptide exhibited significant inhibitory effects against dengue NS2B-NS3pro and virus replication in the infected cells. Therefore, further investigation is necessary to develop the Ltc 1 peptide as a new anti-dengue therapeutic.

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Section: Discussionmentioning

confidence: 99%

Identification of natural antimicrobial agents to treat dengue infection: In vitro analysis of latarcin peptide activity against dengue virus

et al. 2014

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“…Any disruption in functional activities of NS2B-NS3pro complex inhibits viral replication [6]. Different compounds like, chemistry-derived benz[d]isothiazol-3(2H)-one derivatives (2- [2-Phenyl-1-(2-p-cyanophenyl-1,3,4-oxadiazol-5-yl)ethyl]-1,2- benzisothiazol-3(2H)-one (a), 2-[2-Phenyl-1-(2-p-fluorophenyl- 1,3,4-oxadiazol-5-yl)ethyl]-1,2-benzisothiazol-3(2H)-one (b), 2- [2-Phenyl-1-(2-p-methoxyphenyl-1,3,4-oxadiazol-5-yl)ethyl]- 1,2-benzisothiazol-3(2H)-one(c),2-[2-Phenyl-1-(2-phenyl-1,3,4- oxadiazol-5-yl)ethyl]-1,2-benzisothiazol-3(2H)-one (c), 2-[2- Phenyl-1-(2-p-chlorophenyl-1,3,4-oxadiazol-5-yl)ethyl]-1,2- benzisothiazol-3(2H)-one) (d) [7], SK-12 [8] and kalata B1 analogues have been reported as DENV NS2B-NS3 protease inhibitors [9]. But there is no effective drug available for the treatment of DENV infection yet [10].…”

Section: Introductionmentioning

confidence: 99%

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease

Qamar

Mumtaz²,

Ashfaq³

et al. 2014

Bioinformation

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Dengue virus NS2/NS3 protease because of its ability to cleave viral proteins is considered as an attractive target to screen antiviral agents. Medicinal plants contain a variety of phytochemicals that can be used as drug against different diseases and infections. Therefore, this study was designed to uncover possible phytochemical of different classes (Aromatic, Carbohydrates, Lignin, Saponins, Steroids, Tannins, Terpenoids, Xanthones) that could be used as inhibitors against the NS2B/NS3 protease of DENV. With the help of molecular docking, Garcinia phytochemicals found to be bound deeply inside the active site of DENV NS2B/NS3 protease among all tested phytochemicals and had interactions with catalytic triad (His51, Asp75, Ser135). Thus, it can be concluded from the study that these Gracinia phytochemicals could serve as important inhibitors to inhibit the viral replication inside the host cell. Further in-vitro investigations require confirming their efficacy.

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“…Two peptidic inhibitor candidates showed inhibition activity for the protease with low micromolar IC 50 . Several similar peptidic inhibitor candidates, including cyclopeptides (Gao Y, et al, 2010; Xu S, et al, 2012), were found to be active for the NS2B/NS3 protease complex of DENV2, WNV, and YFV with K i (the absolute inhibition constant) as low as 43 nM (Chanprapaph S, et al, 2005; Knox J E, et al, 2006; Nall T A, et al, 2004; Nitsche C, et al, 2012; Schuller A, et al ., 2011; Yin Z, et al, 2006; Yin Z, et al, 2006). Although the in vivo efficacy of these inhibitor candidates has not been verified, the highly charged nature of these peptidic inhibitors may indicate poor bioavailability.…”

Section: Inhibitors For the Ns3/ns2b Proteasementioning

confidence: 99%

The flavivirus protease as a target for drug discovery

Brecher

Zhang

2013

Virol. Sin.

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Many flaviviruses are significant human pathogens causing considerable disease burdens, including encephalitis and hemorrhagic fever, in the regions in which they are endemic. A paucity of treatments for flaviviral infections has driven interest in drug development targeting proteins essential to flavivirus replication, such as the viral protease. During viral replication, the flavivirus genome is translated as a single polyprotein precursor, which must be cleaved into individual proteins by a complex of the viral protease, NS3, and its cofactor, NS2B. Because this cleavage is an obligate step of the viral life-cycle, the flavivirus protease is an attractive target for antiviral drug development. In this review, we will survey recent drug development studies targeting the NS3 active site, as well as studies targeting an NS2B/NS3 interaction site determined from flavivirus protease crystal structures.

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Synthesis and disulfide bond connectivity–activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B–NS3 protease

Cited by 49 publications

References 39 publications

Identification of natural antimicrobial agents to treat dengue infection: In vitro analysis of latarcin peptide activity against dengue virus

Identification of natural antimicrobial agents to treat dengue infection: In vitro analysis of latarcin peptide activity against dengue virus

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease

The flavivirus protease as a target for drug discovery

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