title: Mefenamic acid in combination with ribavirin shows significant effects in reducing chikungunya virus infection in vitro and in vivo.
abstract: Chikungunya virus (CHIKV) infection is a persistent problem worldwide due to efficient adaptation of the viral vectors, Aedes aegypti and Aedes albopictus mosquitoes. Therefore, the absence of effective anti-CHIKV drugs to combat chikungunya outbreaks often leads to a significant impact on public health care. In this study, we investigated the antiviral activity of drugs that are used to alleviate infection symptoms, namely, the non-steroidal anti-inflammatory drugs (NSAIDs), on the premise that active compounds with potential antiviral and anti-inflammatory activities could be directly subjected for human use to treat CHIKV infections. Amongst the various NSAID compounds, Mefenamic acid (MEFE) and Meclofenamic acid (MECLO) showed considerable antiviral activity against viral replication individually or in combination with the common antiviral drug, Ribavirin (RIBA). The 50% effective concentration (EC50) was estimated to be 13 μM for MEFE, 18 μM for MECLO and 10 μM for RIBA, while MEFE + RIBA (1:1) exhibited an EC50 of 3 μM, and MECLO + RIBA (1:1) was 5 μM. Because MEFE is commercially available and its synthesis is easier compared with MECLO, MEFE was selected for further in vivo antiviral activity analysis. Treatment with MEFE + RIBA resulted in a significant reduction of hypertrophic effects by CHIKV on the mouse liver and spleen. Viral titre quantification in the blood of CHIKV-infected mice through the plaque formation assay revealed that treatment with MEFE + RIBA exhibited a 6.5-fold reduction compared with untreated controls. In conclusion, our study demonstrated that MEFE in combination with RIBA exhibited significant anti-CHIKV activity by impairing viral replication in vitro and in vivo. Indeed, this finding may lead to an even broader application of these combinatorial treatments against other viral infections.
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: rothan@um.edu.my.
authors.forename: Hussin A
authors.initials: HA
authors.lastname: Rothan
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: hirbodb83@gmail.com.
authors.forename: Hirbod
authors.initials: H
authors.lastname: Bahrani
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: alirhayim83@gmail.com.
authors.forename: Ammar Y
authors.initials: AY
authors.lastname: Abdulrahman
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: zulq@um.edu.my.
authors.forename: Zulqarnain
authors.initials: Z
authors.lastname: Mohamed
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: ttchong@um.edu.my.
authors.forename: Teow Chong
authors.initials: TC
authors.lastname: Teoh
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: shatraho@um.edu.my.
authors.forename: Shatrah
authors.initials: S
authors.lastname: Othman
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: nurshamimi@um.edu.my.
authors.forename: Nurshamimi Nor
authors.initials: NN
authors.lastname: Rashid
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: noorsaadah@um.edu.my.
authors.forename: Noorsaadah A
authors.initials: NA
authors.lastname: Rahman
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: rohana@um.edu.my.
authors.forename: Rohana
authors.initials: R
authors.lastname: Yusof
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D065632:Chikungunya Fever / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D002646:Chikungunya virus / Q000302:isolation & purification / Q000502:physiology*; D002522:Chlorocebus aethiops; D004359:Drug Therapy, Combination; D006801:Humans; D007668:Kidney / Q000821:virology; D008099:Liver / Q000821:virology; D008469:Meclofenamic Acid / Q000494:pharmacology; D008528:Mefenamic Acid / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D012254:Ribavirin / Q000494:pharmacology*; D013154:Spleen / Q000821:virology; D014709:Vero Cells; D019562:Viral Load / Q000187:drug effects; D053585:Virus Attachment / Q000187:drug effects; D038301:Virus Inactivation / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D008528:Mefenamic Acid; D008469:Meclofenamic Acid; D012254:Ribavirin
keywords: Chikungunya virus; Meclofenamic acid; Mefenamic acid; Non-steroidal anti-inflammatory drugs; Ribavirin