While the protease inhibitor flopped for COVID-19, that doesn’t mean that the line of reasoning of drugs cross-reactive with viral enzymes is a non-starter. Indeed, long ago, the drug AZT that mimicked a sub-component of the nucleotides that make up DNA was developed to inhibit human DNA replication. It was found to cross react with the HIV nucleic acid replication enzyme, thus becoming the first desperately needed breakthrough drug for AIDS, not unlike the process playing out right now for COVID-19. Indeed, just such nucleoside analog drugs from Japan’s Fujifilm (Favipiravir) and the USA’s Gilead Sciences (Remdesivir) are being tested for COVID-19 now, with favipiravir already showing efficacy in a small Chinese study. Both drugs were previously shown to be effective against Ebola virus.
For some reason, drugs that mimic the components of nucleic acids, called nucleotide/nucleoside mimics, tend to cross react across the machinery that copies DNA and/or RNA. This might not be surprising evolutionarily as copying of genetic information (DNA) and expression of genes (RNA) is perhaps the single most fundamental activity of biology. If it's that ancient, it has to be essentially unchanged throughout evolution, right? Still, as our knowledge of the diversity of molecules has grown, it remains surprising that these nucleoside analog drugs cross-react with so many of the DNA/RNA polymerase enzymes.
As to efficacy, these drugs inhibit viral replication without much immune modulation, which matches what is seen in patients, with disease responding early but the drugs being ineffective in the later inflammatory phase of COVID-19. Similarly, the side effects of these drugs, including going far back to AZT, were surprisingly acceptable, given their mechanism of action. It was and remains the thought that DNA/RNA production is so fundamental to biology that such drugs should be highly toxic. In fact, very little DNA synthesis is going on in adult humans at any given time, so adverse events are tissue specific, as usual. Most tissues are quiescent, so although self-renewing tissues like the gut, blood and skin get hit hard, then can recover after the drug is stopped.