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bioRxiv · 10.1101/745455

Antiviral activity of N-ω-Chloroacetyl-L-Ornithine on in vitro replication of Chikungunya virus

Luna-Rojas, L.·Avila-Trejo, A.·Alcantara-Farfan, V.·Rodriguez-Paez, L.·Pastor-Alonso, O.·Aguilar Faisal, L.
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Abstract

The infections causes by Chikungunya virus (CHIKV), family Togaviridae, genus Alfavirus, have become a health problem around the world, due to its widespread occurrence, the high morbidity rate and the absence of vaccines or antiviral treatments. We analyzed a competitive inhibitor of ornithine decarboxylase, enzyme key in the biosynthesis of Polyamines (PAs), N-{omega}-chloroacetyl-L-ornithine (NCAO), as a possible inhibitor of CHIKV replication because intracellular polyamines participate in the transcription and in vitro translation of CHIKV. NCAO does not have any cytotoxic effect on C6/36 cells even at a concentration of 1000M at 72h after post-exposure but in Vero cells the cytotoxic effect was presented above 380M at 48h post-exposure, which was considered when determining the inhibitory effect on viral replication. We demonstrate that NCAO inhibits the replication of CHIKV in Vero and C6/36 cells in a dose-dependent manner causing a decrease in the PFU/mL of at least 4-logarithm (p <0.01) in both cell lines. Viral yields were restored by the addition of exogenous polyamines, mainly putrescine. HPLC analyses it shown that NCAO decrease content of intracellular PAs even though in infected cells mainly decreased spermidine and spermine, so NCAO inhibits CHIKV replication, by depleting the intracellular polyamines in Vero and C6/36 cells, suggesting that this compound is a possible antiviral in CHIKV infections.\n\nImportanceThe infections caused by Chikungunya virus (CHIKV), genus Alfavirus, have become a worldwide health problem, due to its high morbidity rate and the absence of vaccines or antiviral treatments. It is known that CHIKV use intracellular poliamines during transcription and traduction process, so the depletion of intracellular putrescine, spermidine and spermine reduce the viral replication. N-{omega}-chloroacetyl-L-ornithine (NCAO) is known as a competitive inhibitor of ornithine decarboxylase, key enzyme in Polyamines biosynthesis, but no studies have proven its activity on the inhibition of polyamine-dependent viral replication. Here we demonstrate NCAO inhibits in vitro CHIKV replication, so we propose NCAO as an antiviral candidate.

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Luna-Rojas, L., Avila-Trejo, A., Alcantara-Farfan, V., Rodriguez-Paez, L., Pastor-Alonso, O., Aguilar Faisal, L.. 2019-08-24. Antiviral activity of N-ω-Chloroacetyl-L-Ornithine on in vitro replication of Chikungunya virus. https://doi.org/10.1101/745455

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