N -(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity

Barbosa-Lima, Giselle; Pinto, Ligia S. da Silveira; Kaiser, Carlos R.; Wardell, Jámes L.; Freitas, Caroline de; Vieira, Yasmine Rangel; Marttorelli, Andressa; Cerbino-Neto, José; Bozza, Patrı́cia T.; Wardell, Solange M. S. V.; Souza, Marcus V. N. de; Souza, Thiago Moreno L.

doi:10.1016/j.ejmech.2017.01.007

Cited by 23 publications

(17 citation statements)

References 23 publications

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“…Additionally, by medicinal chemistry-driven approaches, a series of new 2,8bis(trifluoromethyl)quinoline and N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives have been proved to inhibit ZIKV replication in vitro with a higher potency than chloroquine or mefloquine [77,78]. More recently, by screening FDA-approved drugs using a cellbased assay, it has been shown that amodiaquine, another antimalarial drug, also has anti-ZIKV activity in cell culture by targeting early events of the viral replication cycle [79].…”

Section: Endosomal Fusionmentioning

confidence: 99%

Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

Saiz¹,

Oya²,

Blázquez³

et al. 2018

Preprint

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Zika virus (ZIKV), a mosquito-borne flavivirus, was an almost neglected pathogen until its introduction in the Americas in 2015, where it has been responsible for a threat to global health, causing a great social and sanitary alarm due to its increased virulence, rapid spread, and an association with severe neurological and ophthalmological complications. Currently, no specific antiviral therapy against ZIKV is available, and treatments are palliative and mainly directed to symptoms relief, such as fever and rash, by administering antipyretics, anti-histamines, and fluids for dehydration. Nevertheless, lately, a great effort has been made to search for antiviral candidates using different approaches and methodologies, ranging from repurposing of specific compounds with known antiviral activity to the screening of libraries and of natural compounds. The identified antiviral candidates include drugs targeting viral components (structural proteins and enzymes), as well as cellular ones. Here, we present an updated review of current knowledge about anti-ZIKV strategies, focusing on host-directed antivirals as a realistic alternative to combat ZIKV infection.

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Section: Endosomal Fusionmentioning

confidence: 99%

Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

Saiz¹,

Oya²,

Blázquez³

et al. 2018

Preprint

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“…Derivatives of mefloquine and chloroquine were synthesized to compare their anti-Zika activity with that of the parent compounds [182,183]. Vero cells were infected with ZIKV isolated from Brazil for 1 h. Cells were subsequently washed and compounds were added.…”

Section: Drug Discovery: Compound Repurposingmentioning

confidence: 99%

Therapeutic Approaches for Zika Virus Infection of the Nervous System

2017

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Zika virus has spread rapidly in the Americas and has caused devastation of human populations affected in these regions. The virus causes teratogenic effects involving the nervous system, and in adults and children can cause a neuropathy similar to Guillain-Barré syndrome, an anterior myelitis, or, rarely, an encephalitis. While major efforts have been undertaken to control mosquito populations that spread the virus and to develop a vaccine, drug development that directly targets the virus in an infected individual to prevent or treat the neurological manifestations is necessary. Rational and targeted drug development is possible since the viral life cycle and the structure of the key viral proteins are now well understood. While several groups have identified therapeutic candidates, their approaches differ in the types of screening processes and viral assays used. Animal studies are available for only a few compounds. Here we provide an exhaustive review and compare each of the classes of drugs discovered, the methods used for drug discovery, and their potential use in humans for the prevention or treatment of neurological complications of Zika virus infection.

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“…ZIKV is mainly transmitted by Aedes aegypti mosquitoes, but blood, sexual, or maternal-fetal modes of transmission have also been observed (5). The potential severity of diseases caused by ZIKV triggered a rapid response from the international community, and drug repurposing efforts led to the identification of FDA-approved drugs showing antiviral activity against ZIKV infection (6,7). Nonstructural protein 5 (NS5), the largest and most conserved flavivirus enzyme, constitutes a prime target in the development of panflavivirus antiviral inhibitors (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Non-nucleoside Inhibitors of Zika Virus RNA-Dependent RNA Polymerase

Gharbi-Ayachi

Santhanakrishnan

Wong

et al. 2020

J Virol

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Zika virus (ZIKV) remains a potentially significant public health concern because it can cause teratogenic effects such as microcephaly in newborns and neurological disease like Guillain-Barré syndrome. Together with efforts to develop a vaccine, the discovery of antiviral molecules is important to control ZIKV infections and to prevent its most severe symptoms. Here we report the development of small non-nucleoside inhibitors (NNIs) of ZIKV RNA-dependent RNA polymerase (RdRp) activity. These NNIs target an allosteric pocket (“N-pocket”) located next to a putative hinge region between the thumb and the palm subdomains, that was originally described for dengue virus (DENV) RdRp. We first tested DENV RdRp N-pocket inhibitors against ZIKV RdRp, introduced chemical modifications into these molecules and assessed their potency using both enzymatic and cell-based assays. The most potent compound has an IC50 value of 7.3 μM and inhibits ZIKV replication in a cell-based assay with an EC50 value of 24.3 μM. Importantly we report four high-resolution crystal structures detailing how these NNIs insert into the N-pocket of ZIKV RdRp. Our observations point to subtle differences in the size, shape, chemical environment and hydration of the N-pocket from ZIKV RdRp compared to DENV RdRp, that are crucial for the design of improved antiviral inhibitors against ZIKV. IMPORTANCE Zika virus belongs to the flavivirus family that comprises several important human pathogens. There is currently neither an approved vaccine nor antiviral drugs available to prevent infection by ZIKV. The NS5 polymerase, which is responsible for replicating the viral RNA genome, represents one of the most promising targets for antiviral drug development. Starting from compounds recently developed against dengue virus NS5, we designed and synthetized inhibitors targeting the Zika virus NS5. We showed that these novel compounds inhibit viral replication by targeting the polymerase activity. High-resolution X-ray crystallographic structures of protein-inhibitor complexes demonstrate specific binding to an allosteric site within the polymerase called the N-pocket. This work paves the way for future structure-based design of potent compounds specifically targeting the ZIKV RNA polymerase activity.

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N -(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity

Cited by 23 publications

References 23 publications

Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

Therapeutic Approaches for Zika Virus Infection of the Nervous System

Non-nucleoside Inhibitors of Zika Virus RNA-Dependent RNA Polymerase

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