Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection

Abstract

e 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.

A screen of approved drugs and molecular probes identifies therapeutics with anti–Ebola virus activity

“…We and others have investigated the utility of screening with approved drugs to identify potential therapeutics that can be used against EBOV and other biological threat agents or emerging diseases (43,(48)(49)(50). Often with such diseases, conventional drug development is challenging because of both cost and ability to perform controlled clinical studies.…”

Middle East Respiratory Syndrome

“…Several agents have shown inhibitory effects against MERS-CoV in cell cultures, includingcyclosporin A, and mycophenolic acid 92,93 . Other compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibit MERSCoV replication in the low-micromolar range (EC50 values 3-8 μM)in vitro 94,95 although whether any of these will be useful in patients is unknown. MERS-CoV-specific peptide fusion inhibitors, which function similarly to the HIV drug, enfuvirtide,diminishvirus replication in cultured cells, providing a novel approach to MERS therapy 96 .…”

A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus

“…Looked at from another perspective “non-antiviral” drugs may be worth following up even though their molecular mechanism is unknown. These compounds may themselves have broad antiviral activity as reports describe modest inhibitory activity against other viruses 10– 13 .…”