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In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases.

ABSTRACT: The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibitory potential of two flavonoids derived from citrus plants: Hesperetin (HST) against NS2B/NS3pro of ZIKV and nsP2pro of CHIKV and, Hesperidin (HSD) against nsP2pro of CHIKV. The flavonoids are noncompetitive inhibitors and the determined IC50 values are in low µM range for HST against ZIKV NS2B/NS3pro (12.6 ± 1.3 µM) and against CHIKV nsP2pro (2.5 ± 0.4 µM). The IC50 for HSD against CHIKV nsP2pro was 7.1 ± 1.1 µM. The calculated ligand efficiencies for HST were > 0.3, which reflect its potential to be used as a lead compound. Docking and molecular dynamics simulations display the effect of HST and HSD on the protease 3D models of CHIKV and ZIKV. Conformational changes after ligand binding and their effect on the substrate-binding pocket of the proteases were investigated. Additionally, MTT assays demonstrated a very low cytotoxicity of both the molecules. Based on our results, we assume that HST comprise a chemical structure that serves as a starting point molecule to develop a potent inhibitor to combat CHIKV and ZIKV co-infections by inhibiting the virus proteases.

SUBMITTER: Eberle RJ

PROVIDER: S-EPMC7932080 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases.

Eberle Raphael J RJ Olivier Danilo S DS Pacca Carolina C CC Avilla Clarita M S CMS Nogueira Mauricio L ML Amaral Marcos S MS Willbold Dieter D Arni Raghuvir K RK Coronado Monika A MA

PloS one 20210304 3

The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibi ...[more]

PMID: 33661906

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Project description:BackgroundThe re-emerging, Aedes spp. transmitted Chikungunya virus (CHIKV) has recently caused large outbreaks in a wide geographical distribution of the world including countries in Europe and America. Though fatalities associated with this self-remitting disease were rarely reported, quality of patients' lives have been severely diminished by polyarthralgia recurrence. Neither effective antiviral treatment nor vaccines are available for CHIKV. Our previous in vitro screening showed that hesperetin, a bioflavonoid exhibits inhibitory effect on the virus intracellular replication. Here, we present a study using the computational approach to identify possible target proteins for future mechanistic studies of hesperetin.Methods3D structures of CHIKV nsP2 (3TRK) and nsP3 (3GPG) were retrieved from Protein Data Bank (PDB), whereas nsP1, nsP4 and cellular factor SPK2 were modeled using Iterative Threading Assembly Refinement (I-TASSER) server based on respective amino acids sequence. We performed molecular docking on hesperetin against all four CHIKV non-structural proteins and SPK2. Proteins preparation and subsequent molecular docking were performed using Discovery Studio 2.5 and AutoDock Vina 1.5.6. The Lipinski's values of the ligand were computed and compared with the available data from PubChem. Two non-structural proteins with crystal structures 3GPG and 3TRK in complexed with hesperetin, demonstrated favorable free energy of binding from the docking study, were further explored using molecular dynamics (MD) simulations.ResultsWe observed that hesperetin interacts with different types of proteins involving hydrogen bonds, pi-pi effects, pi-cation bonding and pi-sigma interactions with varying binding energies. Among all five tested proteins, our compound has the highest binding affinity with 3GPG at -8.5 kcal/mol. The ligand used in this study also matches the Lipinski's rule of five in addition to exhibiting closely similar properties with that of in PubChem. The docking simulation was performed to obtain a first guess of the binding structure of hesperetin complex and subsequently analysed by MD simulations to assess the reliability of the docking results. Root mean square deviation (RMSD) of the simulated systems from MD simulations indicated that the hesperetin complex remains stable within the simulation timescale.DiscussionThe ligand's tendencies of binding to the important proteins for CHIKV replication were consistent with our previous in vitro screening which showed its efficacy in blocking the virus intracellular replication. NsP3 serves as the highest potential target protein for the compound's inhibitory effect, while it is interesting to highlight the possibility of interrupting CHIKV replication via interaction with host cellular factor. By complying the Lipinski's rule of five, hesperetin exhibits drug-like properties which projects its potential as a therapeutic option for CHIKV infection.

Project description:Dengue viruses are the most important arboviral pathogens in the world, which have adapted to human transmission and replication over several hundred years and were initially recognized to cause outbreaks of clinical disease in tropical and subtropical countries by Aedes aegypti mosquitoes. Subsequent global expansion of dengue infection outbreaks has occurred, with millions of cases yearly, probably from a combination of factors including proliferation of international travel and trade, possibly global climate changes, adaptation of the vectors to new environment, and emergence of a new mosquito vector, Aedes albopictus. Chikungunya virus, also transmitted by Aedes mosquitoes, causes a very similar clinical disease but with more prominent arthralgia or arthritis and was originally described in Africa in the 1960s. After a quiescent period of several decades, it reemerged in Africa in 2004 and rapidly spread across the Indian Ocean to involve Asian countries and parts of Europe. However, the past 2 years have seen the emergence of chikungunya virus in the western hemisphere with major outbreaks in the Caribbean and the Americas. Similar to dengue virus, chikungunya virus has adapted to Ae. albopictus mosquitoes which can transmit the disease. Although dengue infection is a more deadly disease especially in young children, chikungunya infection can cause prolonged severe disability and occasionally rare fatalities from encephalitis. No specific treatment is available for either diseases, but development of an effective vaccine for dengue infection is in progress. Until 2007, Zika virus [also transmitted by Aedes species] was associated with only sporadic mild infections in Africa and Asia. In 2007, Zika virus for the first time caused an outbreak beyond Africa and Asia to the Yap Island in the Federated States of Micronesia. Since then Zika virus has spread to French Polynesia, New Caledonia, Cook Islands, and Easter Island in the southeastern Pacific Ocean [Chile] in 2014 and by 2015 to Brazil. By January 2016, it became evident that Zika virus had caused an explosive outbreak in the Americas and the Caribbean with over 30 countries affected. On February 1, 2016, the World Health Organization declared Zika outbreak a global public health emergency. Zika virus infection is most commonly asymptomatic, and 20% of patients may develop a mild viral disease, but of major concern is the reported association of microcephaly in infected pregnant women in Brazil. This chapter explores the history, epidemiology, pathogenesis, clinical features, treatment, and prevention of these rapidly emerging zoonoses.

Dataset Information

In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases.

Publications

In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases.

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