Spin, wheel
Can an antidepressant become a cure for arthritis and heart attack
Polina Loseva, N+1
There are examples of surprisingly versatile drugs in the scientific news every now and then. An antimalarial pill helps with lupus, a cancer drug prevents mice from aging prematurely, a remedy for worms seems to work against covid, and an antidepressant supposedly helps with joint pain. What does it mean? Does this mean that all these diseases are the same thing? Or is it that modern tablets have become so multifunctional?
Imagine that you need to find a cure for a new disease. It is possible to approach the question rationally: find out how it differs from others, figure out what mechanisms underlie it, identify the molecules that are involved in this – and then look for a substance that can block the key molecule for everything that happens.
Such a study may take years or decades. It is much faster (and in the modern world it may be cheaper) to search under a lantern, among already known substances. We sow a thousand cups with a new bacterium, pour a thousand different molecules on them, and we hope that at least one of them will win. And if we are lucky, and this molecule turns out to be a drug familiar to doctors for a long time, then we will save on preclinical trials, and maybe even part of clinical trials: since the drug has been in use for a long time, everyone already knows what side effects to expect from it and for whom it is obviously safe.
This idea is not new: they tried to look for new pills by screening back in the first half of the twentieth century. For example, when it became clear that tuberculosis bacillus was becoming resistant to antibiotics faster than their tests were over, chemists rushed to sort through hundreds of known substances and their derivatives. Two of them – isoniazid and iproniazid – turned out to be deadly for mycobacteria, and the first medicine was at the disposal of doctors.
Mycobacteria (green) inside human macrophages (blue) in control (left) and under the action of isoniazid (right). Minjeong Woo et al. / Frontiers in Immunology, 2018.
And when these drugs began to be tested on humans, it turned out that the second, iproniazid, has unusual side effects. Tuberculosis patients who were prescribed it experienced, according to doctors, "mild euphoria and excitement" – so much so that newspapers described how they, "with holes in their lungs," were dancing in the hospital lobby. Several researchers drew attention to this effect at once – and suggested transferring iproniazid to the front of mental disorders, where there were no pills for depression yet. A year later, a new name was invented for the drug, which was conceived as a weapon against mycobacteria – "antidepressant".
The world of small molecules
Tuberculosis and depression are completely different from each other – except for some symptoms, like a breakdown. The mechanisms that allow iproniazid to work against both diseases also have little in common. They have only one thing in common: both of these processes are triggered by a small chain of atoms – a pair of nitrogen and hydrogen – at the end of the molecule.
When iproniazid is in the body of a tuberculosis patient and penetrates into a mycobacterium cell, the bacterial enzyme katG grabs this chemical group and bites it off, attaching a new tail to the remainder of iproniazid. And in this form, the drug tightly "plugs" another enzyme – InhA – preventing it from building fibers for the cell wall. The tubercle bacillus is dying, deprived of the ability to renew its own shell.
In the second case, the same pair of nitrogen and hydrogen reacts with other, already human enzymes – monoamine oxidases. In brain cells, these enzymes destroy spent neurotransmitters, including serotonin. When iproniazid is glued to them with its nitrogen atoms, monoamine oxidases stop working, there is more serotonin in the neurons – hence the legendary "dances" of tuberculosis patients.
It also happens that the same substance turns out to be multifunctional, like a Swiss knife – and interferes with different chemical processes in different parts. So, apparently, another antidepressant behaves – paroxetine.
There are four closed cycles in its molecule. With one of these rings, it resembles serotonin – and thanks to this, it deceives the serotonin carrier on the membrane of neurons. Grasping for paroxetine instead of serotonin, the carrier protein stops removing the neurotransmitter from the gap between neurons - this is how the "reverse capture" stops. The serotonin signal lasts longer, and the symptoms of depression recede.
On the other hand, paroxetine is similar to ATP – the main carrier of energy in the cell. Therefore, it can deceive another protein, the GRK2 kinase, which uses ATP to transmit a signal: it bites off the phosphate from ATP and attaches it to other cellular proteins, thereby passing the baton on.
GRK2 works, for example, in the heart muscle – it slows down cells, preventing them from being overexcited in response to adrenaline. But when the heart beats weakly for some reason (for example, with a heart attack), adrenaline could help him, and then the work of GRK2 becomes irrelevant. And paroxetine, which blocks it, can get out of the usual role of an antidepressant and act as a cure for heart attacks.
Ultimately, only those who have read the instructions for its use know that paroxetine should fight depression. From the point of view of the cell, there is no "cure for depression" – there is only a molecule, a plug of a special shape, which plugs a particular enzyme.
Looking for a plug
The further the pharmaceutical industry develops, the more the park of small molecules available to doctors grows. If in the 1940s, when chemists were looking for a weapon against tuberculosis bacillus, they had to test hundreds of drugs, then one can imagine how much time they would spend on screening today. It's getting harder to search blindly.
Strictly speaking, even in the middle of the last century, not all searches were truly "blind". One of the teams that rushed to fight tuberculosis noticed that some patients were getting better after taking nicotinamide (vitamin B3). Therefore, the researchers limited their viewing angle to vitamin derivatives and those substances that were somehow similar to it. Among them, in fact, iproniazid was found.
Today, the search criteria look even more complicated. Even if we do not know which substances alleviate the condition of patients with a particular diagnosis, we usually imagine which proteins led to its occurrence. And we are looking for a "molecular plug" for these targets.
After it turned out that paroxetine "cheats" GRK2 (and thereby makes the heart beat), it got into the database of GRK2 blocker substances. And since it is a universal signaling molecule, it is involved in a variety of pathological processes – for example, in cell division. Therefore, paroxetine has recently come up with another mission – to stop the growth of tumors
And then GRK2 was also found in cartilage – there it causes cells to grow and secrete enzymes to rearrange the intercellular substance. When this goes too far, the destruction of cartilage and inflammation of the joints begins, that is, arthritis. And here the antidepressant was also useful – at least, it stopped this process in experimental mice.
And this, it seems, is not the limit of the possibilities of paroxetine. Judging by the fact that doctors often prescribe it "off-label", that is, bypassing the instructions – from premature ejaculation or nerve damage in diabetes – other uses can be found for it. And according to the results of some screenings, he was able to block the penetration of the Ebola virus into cells. However, he is not alone in this: dozens of other substances, including another antidepressant sertraline and the painkiller ibuprofen, are side by side with him. But who knows, perhaps other paroxetine rings will still make themselves known.
Various chemicals, including paroxetine, bind to the glycoprotein on the surface of the ebolavirus. Jingshan Ren et al. / Journal of Medicinal Chemistry, 2018.
Between the chairs
We will hear many more such stories about amazing coincidences and multi-armed substances. And the point here is not in the features of paroxetine, but in the fact that the further away, the cheaper it is to carry out screenings and bombard bacteria or viruses with hundreds of small molecules. And each new unsolved problem only accelerates this search – so, for a year of proximity to the coronavirus, we have already heard about attempts to cope with it with the help of pills for influenza and HIV, malaria and worms, as well as immunosuppressants and even blue dye. By the way, they also offered to treat covid with an antidepressant, although not with paroxetine, but with another one.
However, do not expect that soon doctors will start prescribing us antidepressants (a malaria pill, methylene blue) for all occasions. And the reason for this is not only that most of these attempts to "change" the old molecule do not lead to bright successes in the clinic. And the fact is that no medicine works without side effects. And if it works equally well on several targets, it practically guarantees us that it will have side effects as well.
Iproniazid, which made tuberculosis patients dance, never became a cure for tuberculosis. It is understandable: why burden a healthy nervous system of a person whose problem is limited to bacteria in the lungs? And it is hardly worth feeding paroxetine to those who do not complain of mental disorders. The list of its side effects is so large (among them, for example, weight gain and the risk of bleeding) that it is already called a "pill from hell", despite the impressive commercial and medical success.
Therefore, blind shots and happy coincidences will inevitably be followed by a long laboratory work: the found medicine will be adjusted to a new target, "finished off", weighed with additional chemical groups and cut off the old ones – in search of such an option that will do its new job as best as possible and the old one as bad as possible. And a cure for depression is unlikely to become anything other than a cure for depression - at least that's all it will say on the package.
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