Inhibitory effect of doxycycline against dengue virus replication in vitro

Abstract

Doxycycline is an antibiotic derived from tetracycline that possesses antimicrobial and anti-inflammatory activities. Antiviral activity of doxycycline against dengue virus has been reported previously; however, its anti-dengue properties need further investigation. This study was conducted to determine the potential activity of doxycycline against dengue virus replication in vitro. Doxycycline inhibited the dengue virus serine protease (DENV2 NS2B-NS3pro) with an IC50 value of 52.3 ± 6.2 μM at 37 °C (normal human temperature) and 26.7 ± 5.3 μM at 40 °C (high fever temperature). The antiviral activity of doxycycline was first tested at different concentrations against DENV2 using a plaque-formation assay. The virus titter decreased significantly after applying doxycycline at levels lower than its 50 % cytotoxic concentration (CC50, 100 μM), showing concentration-dependent inhibition with a 50 % effective concentration (EC50) of approximately 50 μM. Doxycycline significantly inhibited viral entry and post-infection replication of the four dengue serotypes, with serotype-specific inhibition (high activity against DENV2 and DENV4 compared to DENV1 and DENV3). Collectively, these findings underline the need for further experimental and clinical studies on doxycycline, utilizing its anti-dengue and anti-inflammatory activities to attenuate the clinical symptoms of dengue virus infection.

The Use of Antimalarial Drugs against Viral Infection

“…It has been reported that these therapies could have activities beyond antimalarial activity, also against viral infectious agents. Surprisingly, in many cases, the administration of antibiotics alone or in combination with other antiviral agents showed significant antiviral activities against different types of viral infections [168][169][170][171]. Despite this evidence, the antiviral mechanisms of action have not been completely investigated.…”

“…This result was confirmed by Rothan and colleagues, who evaluated the replication rate of DENV in an in vitro model of infected cells. They reported that DOX inhibited DENV replication in vitro by reducing viral protease activity and entry into host cells [168]. The same research group determined the inhibitory effects of DOX against CHIKV as well as its possible effect on the virus life cycle in Vero cells when the virus and the drug were administered concurrently to the cells.…”

“…Flaviviridae BVDV(surrogate HCV) Artemisinin in vitro [187,188] Dihydroartemisinin in vitro [63] HCV Artemisinin in vitro [20][21][22] Artesunate in vitro [57] Chloroquine in vitro [148][149][150] ZIKV Mefloquine in vitro [130,131] Chloroquine in vitro [140,141] Amodiaquine in vitro [140] Atovaquone in vitro [166] DENV Quinine sulfate in vitro [66] Mefloquine in vitro [131] Halofantrine in vitro [134] Doxycycline in vitro [168,178] Amodiaquine in vitro [162] CHIKV Doxycycline in vitro [169] Chloroquine in vitro [37,138,139] Atovaquone in vitro [166] Togaviridae SFV Halofantrine in vitro [134] Rhabdoviridae VSV Doxycycline in vitro [170] Orthomyxoviridae IAV Quinine sulfate in vitro [70] In vivo (mouse) [67] Mefloquine in vitro [70] Doxycycline in vivo (mouse) [171] Chloroquine in vitro [159]…”

Molecular Docking Studies of Selected Medicinal Drugs as Dengue Virus-2 Protease Inhibitors

“…The docking methodology was validated using the standard ligands, pinostrobin (1) and 4-hydroxypanduratin A (2), each representing the noncompetitive and competitive inhibitors, respectively. Previous in vitro studies had highlighted the inhibitory potentials for compounds 3, 4 and 5 (Table 1), with compound 3 reported to be non-competitive (Rothan et al 2014b(Rothan et al , 2013. Therefore, the current docking study was conducted not only to determine the ligand poses in the binding sites and the interactions involved, but also to determine the sites to which compounds 4 and 5 were bound and to further validate the inhibitory characteristic of compound 3.…”

“…Antibiotics such as doxycycline (3) and rolitetracycline (5) showed significant inhibitory activity against NS2B-NS3 protease of DENV-2 (Rothan et al 2014b(Rothan et al , 2013. Furthermore, previous finding had shown that non-steroidal anti-inflammatory drug (NSAID), such as meclofenamic acid (4), was not only used to treat symptoms of dengue infections (Kumar et al 2015) but also to inhibit the NS2B-NS3 protease (Rothan et al 2013).…”