Three directly acting
antivirals (DAAs) demonstrated substantial reduction in
COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance
antiviral potency, reduce the emergence of
drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic
drug combinations. While combination
antiviral drug treatments are standard for chronic
RNA virus infections, no
antiviral combination
therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting
antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA
molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses
SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when
molnupiravir, an oral
drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors:
camostat,
avoralstat, or
nafamostat. The combination of
camostat plus
molnupiravir was also effective against the beta and delta variants of concern. The
pyrimidine biosynthesis inhibitor
brequinar combined with
molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of
molnupiravir plus
nirmatrelvir, the
protease inhibitor found in
paxlovid. Pharmacodynamic modeling allowed estimates of
antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of
camostat,
brequinar, and
molnupiravir further increased
antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these
drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral
drug cocktails for at home use at the first sign of an
infection by a coronavirus or other emerging viral pathogens.