It seems that the rate of development of small molecules as drugs for corona lags behind the rate of development of treatments using vaccines and antibodies. An opinion from a medicinal chemist named Derek Leva
[Translation by Dr. Moshe Nachmani]
Seeing the epidemic jump from one country to another is frustrating for chemists developing drugs. Here she has a disease that cries out for medical intervention, and here we are the pharmaceutical chemists, the same people responsible for the discovery of new drugs based on small molecules. So why haven't we already found a treatment for the corona epidemic? so asks Derek Lowe, a pharmaceutical chemist on a website called "The World of Chemistry"
"The truth is that there are a number of such drugs in clinical trials, although no one knows at the moment what their effectiveness will be, or if they will even reach the market in time to make a change in trends. The substances under development are classified into two groups: inhibitors of the viral RNA polymerase as well as inhibitors of the main protease of the virus. The scientists know how to make such inhibitors, so what's the problem? Well, the problem is that each such venture is a completely new addition in itself. All of these enzymes (protease, polymerase) are sufficiently different from each other that a practically effective inhibitor would need to be custom developed. And this customization not only requires the development of a drug that will be particularly effective against the required target, but we must also ensure that it will not be similarly effective against countless human enzymes that we do not wish to inactivate at the same time."
How to damage the virus and not human proteins?
"Polymerase inhibitors, for example, are always derivatives of a nucleoside (from Wikipedia). The drug Remdesivir is an example of such an inhibitor and on May 2020, XNUMX it became the first drug approved by the US Food and Drug Administration (FDA) for the treatment of Corona. The Merck company announced that it will ask the US Food and Drug Administration for emergency approval to use its antiviral drug molnupiravir against the coronavirus. These two substances enter the mechanism of the enzyme as if they were the correct part for the production of the RNA sequence of the virus, however, their combination causes the enzyme to malfunction so that errors begin to accumulate inside it and eventually it breaks down.
It is a heartening sign when a pathogenic virus is treated in this way, but the trick is to find a derivative of such an agent that will be effective against the viral enzyme, while not being particularly effective against other human enzymes that also use nucleosides. Bottom line, there are currently only three candidates in development against the polymerase and protease enzymes of the corona virus, but it is likely that we will need many more attempts until the successful development of truly effective treatments.
As for viral protease inhibitors, they are much more chemically diverse. The main protease of the virus (Mpro) is the first enzyme that manages to act even after the corona virus has infected a cell; However, there are many proteases in human cells, so selectivity is often the challenging part of the field. Pfizer has one such inhibitor in clinical trials (PF-07321332) and its development progress is being watched with great interest. It is possible that the effective treatment will involve a combination of two or more such drugs - the only two viral diseases that we can really treat are Hepatitis C and AIDS, and in both cases a simultaneous combination of different drugs that work by different mechanisms is required. Viruses replicate so quickly that they can evade single-drug treatments. It is likely that the corona virus will not be different.
Either or both of these compounds may fail if they prove to be insufficiently effective or cause many side effects. It must be remembered that most candidate substances to function as drugs fail in the long development stages.
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