Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease

Nitsche, Christoph; Behnam, Mira A. M.; Steuer, Christian; Klein, Christian D.

doi:10.1016/j.antiviral.2012.02.008

Cited by 85 publications

(100 citation statements)

References 17 publications

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“…21 Against this background, we investigated the activity of different retro, retro-inverse, semiretro-inverse, and nonretro dipeptides and tripeptides. 22 The retro tetrapeptide Arg-Arg-Lys-Nle-NH 2 was found to be less active than the tripeptide Arg-Lys-Nle-NH 2 with only one …”

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confidence: 95%

“…These groups were chosen as the most promising caps characterized in our previous work in terms of potency and selectivity. 22,23,29 The thiazolidinedione cap was preferred over the rhodanine cap because the latter is often considered as a fragment with promiscuous binding properties, 30 although the generality of this view has been challenged. 31 Merging the subpocket-specific fragments, associated with the enhancement in inhibitory potency for our most active peptide hybrids 9 (optimized C-terminus) and 33 (optimized N-terminus), resulted in the 20-fold more potent inhibitor 35 (IC 50 = 0.6 μM, K i = 0.4 μM).…”

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confidence: 99%

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C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease

Behnam

Nitsche

Vechi

et al. 2014

ACS Med. Chem. Lett.

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Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC 50 = 0.6 μM, K i = 0.4 μM). First, a large number of natural and non-natural amino acids were screened at the C-terminal position of the previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH 2 ). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH 2 , IC 50 = 13.3 μM), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC 50 = 3.3 μM). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC 50 = 2.5 μM). This approach led to the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengue protease. KEYWORDS: Dengue virus, protease inhibitor, peptide, fragment merging D engue virus (DENV), with its four common serotypes (DENV 1−4), is considered the most important diseasecausing arbovirus in tropical and subtropical regions and a major public health concern. A recent study estimates a global infection burden of 390 million cases in 2010, a more than 3-fold higher number than reported previously by the World Health Organization. 1,2 Increasing prevalence of dengue infections worldwide has been associated with the geographical spread of Aedes mosquitoes, the primary transmitting vector, probably as a result of global warming and climate changes. 3 Currently, vaccines or antiviral agents against DENV remain unavailable. Viral proteases are extremely relevant for the development of antiviral drugs. 4 Highly successful examples are the hepatitis C virus (HCV) NS3 protease inhibitors, such as boceprevir and telaprevir, 5 and the HIV protease inhibitors. 6 DENV protease is regarded as a similarly promising target for drug discovery efforts against dengue virus infections. 7 The enzyme is critical for the viral replication cycle. It posttranslationally cleaves the viral polyprotein, encoded by a single stranded RNA, into three structural and seven nonstructural (NS) proteins. The proteolytically competent NS3-NS2B complex consists of the NS3 serine protease domain and the hydrophilic core sequence of NS2B as cofactor. 8,9 Published inhibitors against DENV protease range from small molecule nonpeptidic inhibitors, 10−13 so far not capable of achieving sufficient target inhibition, to substrate-mimicking peptidic inhibitors. 14−18 The latter class benefits from improved molecular recognition because of its similarity to the natural substrate, which offers higher selectivity and activity, reaching the low micromolar range and even the nanomolar range when combined with an electrophilic warhead. 18 However, the promising in vitro binding affinities come at the expense of pharmacokinetic properties, such as membrane permeability and metabolic stability, which is challenged by ...

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confidence: 95%

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confidence: 99%

C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease

Behnam

Nitsche

Vechi

et al. 2014

ACS Med. Chem. Lett.

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“…DENV has also emerged as an increasing fitness problem in the world for which no specialized drug is available in the market. The non-structural protein NS3 protease of DENV has already been recognized as a potential therapeutic target for the discovery and development of novel antiviral agents against DENV infection [8,17,22,23,36,37]. NS3 molecule of DENV is comprised of a protease (NS3pro) and a helicase (NS3hel) domain, where the NS3pro domain relies on a cofactor, NS2B for their catalytic action and serves as a center for the assembly of the DENV replication complex and also modulates viral pathogenesis and the host immune response [4,6,11,18,19].…”

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confidence: 99%

Identification of new potent inhibitors of dengue virus NS3 protease from traditional Chinese medicine database

et al. 2016

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Dengue virus (DENV) has emerged as an increasing fitness problem in the world for which no specialized drug is available. The non-structural protein NS3 protease of DENV has already been recognized as a potential therapeutic target for the discovery and development of novel antiviral agents against DENV infections. In this study, we employed the virtual screening technique to explore the potent inhibitors of DENV NS2B/NS3pro from Traditional Chinese Medicine (TCM) database. Total 200 inhibitors from TCM against DENV NS3pro were screened and only five TCM compounds like eriodictyol 7-O-glucuronide, luteolin 8-C-beta-glucopyranoside, (-)-epicatechin-3-O-gallate, 6-O-trans-p-coumaroylgeniposide and luteolin-7-O-glucoside were selected for further analysis which showed binding energies, -7.000, -7.380, -7.380, -7.440 and -7.440 kcal/mol, respectively. The findings of this study suggest that these five TCM compounds can be considered as potent inhibitors for DENV NS2B/NS3pro for the development of anti-dengue drugs.

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“…Polyprotein comprising of three structural (C, prM, M) and seven non-structural proteins (NS1,NS2A,NS2B,NS3,NS4A,NS4B and NS5) is further processed by host proteases and NS2B-NS3 viral protease, a major characteristic of the viral life cycle and replication performance. Consequently, the protease inhibition can be a successful way to fight against DENV infection [10][11][12][13][14] . Located in the N-terminal region, NS3 is a multifunctional protein that comprises of 180 amino acids of NS3 protease.…”

Section: Introductionmentioning

confidence: 99%

High throughput virtual screening based discovery of dengue protease inhibitor

et al. 2017

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High throughput virtual screening (HTVS) has been proved a successful tool for getting LEADs in drug design and discovery. In an attempt to design new Dengue protease inhibitors, we performed HTVS using Zinc13 database containing 13,195,609 drug-like molecules. ZINC42678127 was identified as potential HIT against Dengue protease.It's shape and electrostatic complimentary was found to be 0.608 and 0.078, respectively. Qikprop analysis of the compound complied with the Rule of Five (Ro5) and other druglikeliness properties. Binding mode analysis of docked conformer of ZINC42678127, displayed favorable interaction with the active site residues of DENV protease. The identified HIT has a potential to become a LEAD against Dengue protease.

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Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease

Cited by 85 publications

References 17 publications

C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease

C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease

Identification of new potent inhibitors of dengue virus NS3 protease from traditional Chinese medicine database

High throughput virtual screening based discovery of dengue protease inhibitor

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