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There are four drugs being tested for effectiveness against COVID-19 in the SOLIDARITY trial. Three of them have obvious potential mechanisms of action:

  • Remdesivir is an RNA polymerase inhibitor. It might stop the virus from multiplying once it infects a cell.
  • Hydroxychloroquine may interfere with the spike protein the virus uses to attach to cells.
  • Interferon beta has general antiviral effects.

But I can't find anything that would explain why the Lopinavir/Ritonavir combination is expected to do anything. Both drugs appear to be protease inhibitors that are fairly specific to HIV, while SARS-CoV-2 isn't even in the same general group of viruses as HIV.

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The NEJM editorial that accompanied that issue says:

One antiviral-drug candidate is a combination of the HIV protease inhibitors lopinavir and ritonavir. Lopinavir, which acts against the viral 3CL protease, has modest antiviral activity against SARS-CoV-2.

A quick search shows that SARS-CoV 3CL protease was the topic of some more in-depth investigations, including a theoretical Thai study of how of lopinavir might act on the 3CLpro of SARS:

it was found that a mixture of two HIV-1 proteinase inhibitors, lopinavir and ritonavir, exhibited some signs of effectiveness against the SARS virus. To understand the fine details of the molecular interactions between these proteinase inhibitors and the SARS virus via complexation, molecular dynamics simulations were carried out for the SARS-CoV 3CLpro free enzyme (free SARS) and its complexes with lopinavir (SARS–LPV) and ritonavir (SARS–RTV). The results show that flap closing was clearly observed when the inhibitors bind to the active site of SARS-CoV 3CLpro.

[From:] Nukoolkarn et al. "Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors" J Theor Biol.

It's "above my pay grade" to comment whether that makes any sense or not as a practical approach to SARS (or Covid-19) medication, but the paper notes that lopinavir has a similar effect on the HIV protease:

Similarly, this kind of flap (loop) closing was also observed when inhibitors bind in the active site of HIV-1 protease (Hornak et al., 2006a, Hornak et al., 2006b).

As noted on Protopedia

Drugs that inhibit HIV protease prevent the virus from replicating, and are crucial components of anti-HIV therapies.

The proteolytic active site of HIV protease is covered by two "flaps". It is believed that these flaps must open to enable substrate polyprotein to enter the active site. Drugs that inhibit HIV protease tend to "lock" the flaps closed.

So I think they were/are hoping that 3CL plays a similarly vital role for SARS and Covid-19 virus replications, and so that drugs that close it will inhibit virus replication.

There seem to be other researchers who have considered this approach for the SARS-CoVs, so perhaps it has some merit:

One promising approach is to develop small molecule inhibitors of the essential major polyprotein processing protease 3Clpro. Here we report a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160,000 possible naturally occurring tetrapeptides.

There's even a library-compound-search paper like that (i.e. trying to find molecules that would inhibit its 3CL) for SARS-CoV-2 out already (published March 26) by Chinese and Saudi researchers:

The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.

However, this latter paper also notes that there are some key differences between the SARS-CoV and SARS-CoV-2 3CL proteases, so compounds that work against one might not be so effective against the other:

results revealed that the SARS-CoV-2 3CLpro receptor-binding pocket conformation resembles that of the SARS-CoV 3CLpro binding pocket and raises the possibility that inhibitors intended for SARS-CoV 3CLpro may also inhibit the activity of SARS-CoV-2 3CLpro.

To test this hypothesis, we docked (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide), a potential noncovalent inhibitor of SARS-CoV 3CLpro named ML188 [35], with the SARS-CoV-2 3CLpro homology model. We also docked ML188 with the SARS-CoV 3CLpro structure (PDB ID: 3M3V) as a reference, and ML188 bound strongly to the receptor binding site of SARS-CoV 3CLpro. The inhibitor targets the Cys-His catalytic dyad (Cys-145 and His-41) along with the other residues, and the docking score (S = −12.27) was relatively high. However, surprisingly, ML188 did not show significant binding to the catalytic dyad (Cys-145 and His-41) of SARS-CoV-2, and the docking score (S = −8.31) was considerably lower (Fig. S3).

This paper also investigated (in the theoretical/computational sense) three other drugs of that kind that might work on the SARS-CoV-2 3CL: Nelfinavir, Prulifloxacin and Colistin. Nelfinavir is also a protease inhibitor used to treat HIV-1 and Wikipedia says it's also being investigated for COVID-19, but I haven't checked the details. Interestingly perhaps, lopinavir is not mentioned at all in this SARS-CoV-2 inhibitor screening study. I couldn't tell you exactly why, but it might be because there are at least six "1st gen" protease inhibitors used in HIV treatment (and some "2nd gen" ones) so they probably just picked one for this study as representative.

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