A perspective on targeting non-structural proteins to combat neglected tropical diseases: Dengue, West Nile and Chikungunya viruses

Bhakat, Soumendranath; Karubiu, Wilson; Jayaprakash, Venkatesan; Soliman, Mahmoud E. S.

doi:10.1016/j.ejmech.2014.10.010

Cited by 37 publications

(41 citation statements)

References 108 publications

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“…Some compounds within this series inhibited DENV replication in both viral protein and mRNA levels, without significant cell cytotoxicity [7]. In parallel, a recent review discussed the potential of targeting non-structural proteins and more specifically proteases for combating neglected diseases as caused by arboviruses with in particular Dengue virus [8]. In addition, inhibition of host factors or processes indispensable for viral proliferation have been studied at several instances.…”

Section: Introductionmentioning

confidence: 99%

Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus

Saudi

Zmurko

Kaptein

et al. 2016

European Journal of Medicinal Chemistry

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High-throughput screening of a subset of the CD3 chemical library (Centre for Drug Design and Discovery; KU Leuven) provided us with a lead compound 1, displaying low micromolar potency against dengue virus and yellow fever virus. Within a project aimed at discovering new inhibitors of flaviviruses, substitution of its central imidazole ring led to synthesis of variably substituted pyrazine dicarboxylamides and phthalic diamides, which were evaluated in cell-based assays for cytotoxicity and antiviral activity against the dengue virus (DENV) and yellow fever virus (YFV). Fourteen compounds inhibited DENV replication (EC50 ranging between 0.5 and 3.4 μM), with compounds 6b and 6d being the most potent inhibitors (EC50 0.5 μM) with selectivity indices (SI) > 235. Compound 7a likewise exhibited anti-DENV activity with an EC50 of 0.5 μM and an SI of >235. In addition, good antiviral activity of seven compounds in the series was also noted against the YFV with EC50 values ranging between 0.4 and 3.3 μM, with compound 6n being the most potent for this series with an EC50 0.4 μM and a selectivity index of >34. Finally, reversal of one of the central amide bonds as in series 13 proved deleterious to the inhibitory activity.

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Section: Introductionmentioning

confidence: 99%

Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus

Saudi

Zmurko

Kaptein

et al. 2016

European Journal of Medicinal Chemistry

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“…In addition to its role as a cofactor of the viral polymerase complex, nsP2 is a virulence factor [4].…”

Section: Nsp2mentioning

confidence: 99%

“…The recently solved crystal structure of CHIKV nsP2 might function as a crucial starting point for the development of novel antivirals targeting CHIKV [4,7,61,62]. The complete nucleotide sequence of the CHIKV genome revealed that nsP2 is the largest nonstructural protein: 798 amino acids long with a large, net positive charge [62].…”

Section: Nsp2mentioning

confidence: 99%

“…Neglected tropical diseases (NTDs) compose a group of infections that primarily affects the world's poorest populations; they continue to be the leading cause of morbidity and mortality among the poorest people in developing countries [1][2][3][4]. NTDs affect more than one billion individuals who have inadequate access to safe water, sanitation, and appropriate housing.…”

Section: Introductionmentioning

confidence: 99%

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Potential Antivirals: Natural Products Targeting Replication Enzymes of Dengue and Chikungunya Viruses

Oliveira

Teixeira

Oliveira

et al. 2017

Preprint

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Abstract:Dengue virus (DENV) and chikungunya virus (CHIKV) are reemergent arboviruses that are transmitted by mosquitoes of the Aedes genus. During the last several decades, these viruses have been responsible for millions of cases of infection and thousands of deaths worldwide. Therefore, several investigations were conducted over the past few years to find antiviral compounds for the treatment of DENV and CHIKV infections. One attractive strategy is the screening of compounds that target enzymes involved in the replication of both DENV and CHIKV. In this review, we describe advances in the evaluation of natural products targeting the enzymes involved in the replication of these viruses.

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“…A closer precedent is the development of therapeutics for Dengue virus (DENV) and West Nile virus (WNV) that target the non-structural proteins that are essential for viral replication; which is being pursued by many research groups and includes development of inhibitors for the NS2B/NS3 protease, the NS3 helicase domain, and the NS5 methyl transferase and RNA polymerase domains (Bhakat et al, 2014; Lim et al, 2013; Noble and Shi, 2012). Although there is promising progress, particularly for Dengue, most research is still in the early lead phase, with efficacy still far behind the development of therapeutics for the related HCV.…”

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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A perspective on targeting non-structural proteins to combat neglected tropical diseases: Dengue, West Nile and Chikungunya viruses

Cited by 37 publications

References 108 publications

Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus

Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus

Potential Antivirals: Natural Products Targeting Replication Enzymes of Dengue and Chikungunya Viruses

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

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