Current Approaches in Antiviral Drug Discovery Against the Flaviviridae Family

Baharuddin, Aida; Hassan, Aziz; Sheng, Gan Chye; Nasir, Shah Bakhtiar; Othman, Shatrah; Yusof, Rohana; Othman, Rozana; Rahman, Noorsaadah Abdul

doi:10.2174/13816128113199990635

Cited by 23 publications

(13 citation statements)

References 165 publications

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“…Three antiviral candidate therapies, including ribavirin, interferon α (IFN-α), and WNV-specific immunoglobulin are discussed below. Emerging therapies that lack human data, including nucleic acid inhibition, peptides, and small molecules targeting viral translocation, replication, or protease activity, have been reviewed recently and are not discussed here 87,88…”

Section: Treatmentmentioning

confidence: 99%

A review of the epidemiological and clinical aspects of West Nile virus

Gray¹,

Webb²

2014

IJGM

117

112

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The resurgence of West Nile virus (WNV) in North America and Europe in recent years has raised the concerns of local authorities and highlighted that mosquito-borne disease is not restricted to tropical regions of the world. WNV is maintained in enzootic cycles involving, primarily, Culex spp. mosquitoes and avian hosts, with epizootic spread to mammals, including horses and humans. Human infection results in symptomatic illness in approximately one-fifth of cases and neuroinvasive disease in less than 1% of infected persons. The most consistently recognized risk factor for neuroinvasive disease is older age, although diabetes mellitus, alcohol excess, and a history of cancer may also increase risk. Despite the increasing public health concern, the current WNV treatments are inadequate. Current evidence supporting the use of ribavirin, interferon α, and WNV-specific immunoglobulin are reviewed. Nucleic acid detection has been an important diagnostic development, which is particularly important for the protection of the donated blood supply. While effective WNV vaccines are widely available for horses, no human vaccine has been registered. Uncertainty surrounds the magnitude of future risk posed by WNV, and predictive models are limited by the heterogeneity of environmental, vector, and host factors, even in neighboring regions. However, recent history has demonstrated that for regions where suitable mosquito vectors and reservoir hosts are present, there will be a risk of major epidemics. Given the potential for these outbreaks to include severe neuroinvasive disease, strategies should be implemented to monitor for, and respond to, outbreak risk. While broadscale mosquito control programs will assist in reducing the abundance of mosquito populations and subsequently reduce the risks of disease, for many individuals, the use of topical insect repellents and other personal protective strategies will remain the first line of defense against infection.

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Section: Treatmentmentioning

confidence: 99%

A review of the epidemiological and clinical aspects of West Nile virus

Gray¹,

Webb²

2014

IJGM

117

112

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“…At the moment, patients with severe cases of Flavivirus infections are treated only by supportive care, which includes intravenous fluids, hospitalization, respiratory support, and prevention of secondary infections. [14] In fact, despite worldwide extensive research and public health concern associated with Flavivirus diseases, no specific/routine treatment is available today to combat any Flavivirus infections, the sole exception being constituted by new drugs (e.g., simeprevir and sofosbuvir) currently in clinical trials for hepatitis C. [15,16] Consequently, there is an urgent need for new lead compounds that efficiently target distinct stages of the viral replication cycle in a virus-specific way.…”

mentioning

confidence: 99%

A combined in silico / in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems

Carta

Briguglio

Piras

et al. 2016

European Journal of Medicinal Chemistry

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In this work, we present and discuss a comprehensive set of both newly and previously synthesized compounds belonging to 5 distinct molecular classes of linear aromatic N-polycyclic systems that efficiently inhibits bovine viral diarrhea virus (BVDV) infection. A coupled in silico/in vitro investigation was employed to formulate a molecular rationale explaining the notable affinity of all molecules to BVDV RNA dependent RNA polymerase (RdRp) NS5B. We initially developed a three-dimensional common-feature pharmacophore model according to which two hydrogen bond acceptors and one hydrophobic aromatic feature are shared by all molecular series in binding the viral polymerase. The pharmacophoric information was used to retrieve a putative binding site on the surface of the BVDV RdRp and to guide compound docking within the protein binding site. The affinity of all compounds towards the enzyme was scored via molecular dynamics-based simulations, showing high correlation with in vitro EC50 data. The determination of the interaction spectra of the protein residues involved in inhibitor binding highlighted amino acids R295 and Y674 as the two fundamental H-bond donors, while two hydrophobic cavities HC1 (residues A221, I261, I287, and Y289) and HC2 (residues V216, Y303, V306, K307, P408, and A412) fulfill the third pharmacophoric requirement. Three RdRp (K263, R295 and Y674) residues critical for drug binding were selected and mutagenized, both in silico and in vitro, into alanine, and the affinity of a set of selected compounds towards the mutant RdRp isoforms was determined accordingly. The agreement between predicted and experimental data confirmed the proposed common molecular rationale shared by molecules characterized by different chemical scaffolds in binding to the BVDV RdRp, ultimately yielding compound 6b (EC50 = 0.3 μM; IC50 = 0.48 μM) as a new, potent inhibitor of this Pestivirus.

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“…Considering the global threat of flaviviral pandemics, specific treatments are craved for. 44 3.1.1 ZIKA virus ZIKV is transmitted to humans by mosquito bites: in adults, it usually causes mild to no symptoms, while it might be devastating if contracted during pregnancy, as it is related to microcephaly in the unborn child. Several G4 forming sequences have been discovered in the positive strand of the ZIKV genome, while the negative one is devoid of PQSs.…”

Section: Flavivirusesmentioning

confidence: 99%