Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection

Abstract

Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies.

FIG 1

Flowchart of screening procedure. A library of 290 compounds was screened at three doses for activity against MERS-CoV. Seventy-two compounds that had activity against MERS-CoV were subsequently screened against both MERS-CoV and SARS-CoV. Twenty-seven compounds showed activity (>50% inhibition) against both viruses, while 33 compounds were active against only MERS-CoV. A 102-compound subset was screened against SARS-CoV, leading to 6 compounds that were active against only SARS-CoV.

FIG 2

Antiviral activity of chlorpromazine hydrochloride and triflupromazine hydrochloride. (A) Chemical structures of the compounds. Vero E6 cells were infected with MERS-CoV or SARS-CoV at an MOI of 0.1 or 1, respectively, and treated for 48 h with eight doses of chlorpromazine hydrochloride (B) or triflupromazine hydrochloride (C). Antiviral activity is shown in blue, and cytotoxicity is shown in red. EC₅₀s are indicated. Results are representative of one experiment (means ± standard errosr of the means [SEM]; n = 2).

FIG 3

Antiviral activity of dasatinib and imatinib mesylate. Vero E6 cells were infected with MERS-CoV or SARS-CoV at an MOI of 0.1 or 1, respectively, and treated for 48 h with eight doses of dasatinib (A) or imatinib mesylate (B). Antiviral activity is shown in blue, and cytotoxicity is shown in red. EC₅₀s are indicated. Results are representative of one experiment (means ± SEM; n = 2).

FIG 4

Antiviral activity of gemcitabine hydrochloride and toremifene citrate. Vero E6 cells were infected with MERS-CoV or SARS-CoV at an MOI of 0.1 or 1, respectively, and treated for 48 h with eight doses of gemcitabine hydrochloride (A) or toremifene citrate (B). Antiviral activity is shown in blue, and cytotoxicity is shown in red. EC₅₀s are indicated. Results are representative of one experiment (means ± SEM; n = 2).