Repositioning of existing FDA-approved drugs as novel antivirals

Keywords: drug repositioning, drug repurposing, SARS, cowpox, vaccinia, flu, avian flu, H1N1, H3N2, measles, hepatitis B, Hep B, tipepidine (Asverin), bleomycin, butoconazole, sulconazole (Excelderm), pramipexole (Mirapex), candesartan, polymerase PAC-PB1N, glycoprotein B

The following is the summary of antiviral screen completed at The Southern Research Institute (https://southernresearch.org/).  The Southern Research Institute has biosafety level 3 (BSL-3) facilities to conduct research projects involving viral pathogens that can cause serious or deadly diseases.

Briefly, the task was to select viral protein targets, based on the breadth of viral types and low probability of developing resistance to a drug over time.  The selected targets were then used in Q-MOL virtual ligand screening with a library of existing FDA-approved drugs.

The following protein targets were selected for Q-MOL protein-ligand docking:

The library of FDA-approved drugs, containing 3655 compounds, was used for docking. The figure below shows an actual docking curve for one of the targets (Target B):

For each protein target, 25 best (lowest energy) compounds were selected and send to the Southern Research Institute for antiviral screening (total 50 compounds).

The table below represents the summary of the screening results:

Note the correlation between the origin of a viral target and affected virus type: the origin of Target A is avian influenza H5N1 and identified hits against this protein are targeting influenza H1N1 and H3N2 viruses.

The most interesting hit is Candesartan in its active form demonstrating 40 nM EC₅₀ of replication inhibition of Hepatitis B virus. The antiviral activity of candesartan was further confirmed in the secondary assays:

The secondary assays were completed in Georgetown University screening center (PI – Dr. Brent Korba).

The important parameter, computed in the secondary assays, is selectivity index (SI).  The selectivity index is used to evaluate the potential effectiveness and safety of a compound by comparing its toxicity to healthy cells versus its activity against a target such as viruses.  The higher the SI value, the better and safer the compound is considered to be. This indicates that a much lower concentration is needed to achieve the desired effect on the target compared to the concentration that harms healthy cells, e.g. in our case candesartan concentration required to achieve 50% virus elimination is 2240 times lower (SI₅₀).

Caution: all antiviral screening experiments were completed on model cells; in vivo studies are required for final efficacy estimations.

Anton Cheltsov, Ph.D.