To fight SARS-COV-2 we use vaccines which train our immune system against viral epitopes like the external S(pike) protein. Since these structures change a lot, would it not have been a better idea to develop drugs which inhibit viral replications (such as protease inhibitors do with HIV)?

I know that vaccines make sense, but couldn`t it make sense to give such antivirals a shot?

Coronaviruses caused quite some trouble within the last years (SARS, MERS), to focus on more genetically stable structures would make sense. Who knows, perhaps there is going to be a new pandemic in the near future....

My question is, are these structures really genetically more stable? And If so, why are there no drugs yet? I know drug development takes normally quite long (over a decade). Why is it more difficult to develop antivirals than to develop vaccines?

Best wishes, Mourinho_1

  • $\begingroup$ Yes, this is correct for (at least some) viruses. E.g., in HIV pol and gag genes are singificantly more conserved, while the genes responsible corresponding to proteins involved in viral attachment to cells. Some elements even explicitly have word variable in them, such as variable loops. $\endgroup$ Sep 20 '21 at 7:30
  • $\begingroup$ Thanks a lot for your answer. I have some issues finding a paper about this. Could you help me out? I would highly appreciate it. Best wishes, Mourinho_1 $\endgroup$
    – Mourinho_1
    Sep 20 '21 at 8:49

The answer is that drugs and vaccines do different things.

Drugs treat the problem (sometimes before it starts - this is known as a prophylactic), whereas vaccines are intended to prevent the problem from starting in the first place, so vaccines are a form of prophylactic themselves.

One of the problem with drugs is that the vast majority of them have some side-effects, some serious, some not. In many cases, long-term taking of a drug will result in some damage to the taker. How serious this damage is depends strongly on the drug, how long it is being taken for, and how much is being administered. Vaccines, on the other hand, are generally well tolerated usually being comprised of either proteins from the species of interest or weakened/inactive forms of the pathogen they are preventing. Vaccines encourage your body to prevent harm from an invading pathogen by giving it something to recognize before an actual infection happens.

Vaccines are generally developed against parts of the infecting organism that the body can see - in the case of enveloped viruses (like SARS-CoV-2 and Influenza), this is the bits that poke through the viral envelope, such as the S (spike) protein or HA/NA of influenza.

These sites do change a lot and the virus is under selective pressure to evade the antibodies that bind to these sites, leading to breakthrough infections. However, the same happens for drugs - the virus is again under selective pressure from the drug, so drug resistance happens. Indeed, we have seen this happen in real-time with influenza, where the first generation of anti-influenza drugs (called Amantadines) are no longer effective because of changes in the proteins they target.

As it so happens, there is one drug for SARS-CoV-2 called Remdesivir. This is a nucleoside analogue, that pretends to be one of the nucleobases that comprise the genomes of RNA viruses, and it is effective against a range of RNA viruses. However, check out the side effects part... Resistance to this drug has been observed in the lab for SARS-CoV-2 and other viruses. You might think that it would be pretty hard to develop resistance to something that behaves as part of your genome, because the proteins that process the genome are fairly stable - they can only tolerate a few changes before they are no longer functional, but we still see resistance developing because there is some wiggle-room.

Drugs are being developed to target stable parts of the genome or bits that can't be mutated for a range of viruses, but it is very difficult to do because it requires massive screening of compounds for effectiveness, then screening for toxicity/side effects etc in the host(s), then further development to make the drug deliverable in a form that the body can uptake and transport and finally clinical trials.

  • 1
    $\begingroup$ Since viruses typically hijack much of the cell's own machinery, and even viral-encoded proteins are often closely related to similar functional proteins of the cell, it's difficult to identify an anti-viral that doesn't also have a negative effect on the cell. With bacterial infections, bacteria have important components (like cell walls) that are missing in human cells and so can be targeted with more impunity. Many antibiotics target such bacterial-specific molecules. $\endgroup$
    – Armand
    Sep 20 '21 at 3:03
  • $\begingroup$ @Armand Yes exactly. However, people are working on developing drugs for things like the influenza RdRP active site, which can't really mutate without losing functionality, but it's really really hard to do, and there's still evidence of resistance mutations. $\endgroup$
    – bob1
    Sep 20 '21 at 8:28

As I have already mentioned in the comments, the mutation rates are indeed different, at least in some viruses. As an example we can take HIV, where pol, gag, and other genes essential for viral replication and interference with the cellular machinery are singificantly more conserved than the env gene, coding for the viral envelope.

Mutations vs. substitutions
To be more precise, one has to distinguish between the mutation rates and the substitution rates. The former are actually pretty much the same along the genome, since they are determined by the chemical processes. These are the rates that one observes in an in vitro experiment where virus is allowed to replicate for one generation, and thus the question of the viability of the new virions does not arise.

Substitution rate is what one measures in vivo, since mutations in the genes needed for replication, such as the polymerase gene, result in "dead" virions, which are present in the blood samples at negligeable concentrations. On the other hand, the substitutions in the envelope gene, which are responsible for the constant adaptation to the host, present much higehr variety.

As a consequence, when looking for the articles on the subject, it makes more sense to look for fitness rather than mutation rate data. Such as, e.g., right panel of figure 5 in this article: enter image description here

  • $\begingroup$ Thats so cool! Thanks a lot! $\endgroup$
    – Mourinho_1
    Sep 20 '21 at 17:26
  • $\begingroup$ My understanding is that if you look at the viral genome population and do a mutational analysis, generally there isn't a lack of mutations, substitutions etc in those conserved genes, it is purely that the viruses that are mutated at those essential sites aren't viable and don't produce an infection in subsequent hosts, hence the conservation. $\endgroup$
    – bob1
    Sep 20 '21 at 20:05
  • $\begingroup$ @bob1 Not sure how this differs from the difference between the mutations and the substitutions as explained in my answer. Btw, I liked your answer - mine was intended just to give one example. $\endgroup$ Sep 21 '21 at 4:46
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    $\begingroup$ @RogerVadim there isn't much difference - it's the old quasi-species problem but I believe you can measure it outside of a single-cycle infection process. I like your answer too - it's a lovely example of a classic virology problem, that I hadn't considered in my answer. $\endgroup$
    – bob1
    Sep 21 '21 at 9:04

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