Plant derived natural products are an invaluable help in drug discovery. Many compounds that we use as medicines were first isolated from plants or at least are inspired by plant chemicals. In some cases, indeed, these compounds work just fine as they are, while in others it is possible to change or improve their activity or other important parameters, by making small chemical modifications.
A few days ago, an editorial about natural products that could help against COVID-19 was published in Nature Plants (1).This gave me the inspiration to publish here a follow up to my previews post “Debunking fake news about the use of plants or plant derived compounds in the treatment or prevention of SARS-CoV-2 infection”, which also included a small paragraph on the same topic.
The drug discovery and development process is shortly, but effectively, summarized in the editorial: “researchers first discover a drug molecule with potential therapeutic activity against a certain target, then optimize its structure and validate its function using in vitro experiments followed by animal and clinical trials“. This requires very long and consequently is not really compatible with the current emergency. Therefore, all the ongoing clinical trials are using pre-existing drugs. We talk in this case of drug repurposing (or repositioning): a drug already in use is taken into consideration for different therapeutic purposes. This means that we have already most of the information that is required for the drug to be used, we “just” need to verify if it works in the specific instance.
By having a look at clinical trial databases, like the European Register of Clinical Trials (2) or the NIH Registry (3),a we can see that the only plant derived compounds (or related chemicals) that are currently being tested in a significant amount of trials are colchicine and quinine analogues,b i.e. chloroquine, hydroxychloroquine, and (to a lesser extent) mefloquine.
Quinine analogues
Chloroquine, hydroxychloroquine and mefloquine are not natural compounds, but, as previously said, they are analogues of quinine, which is the actual natural product. Quinine was isolated from the plant Cinchona officinalis and is produced by several other plants of the same genus. The Cinchona bark was used in South America to treat the symptoms of fever and in the XVII century this did not go unnoticed by the Spanish conquerors that imported its use to Europe, as treatment against malaria (4). Quininec was then isolated exactly two centuries ago from the bark of the plant and has long been used in the prophylaxis and treatment of the disease (4,5). It is not only working as antipyretic, but it also exhibits selective toxicity against Plasmodium species (the causing agents of malaria).
This alkaloid,d along with others isolated from the same plant, drew the attention of many scientists, including Louis Pasteur.e However, for many years its only source was the Cinchona bark, which was mainly imported from South America, until the plant was also introduced to India and Java by European colonizers. Java, especially, became the main supplier of this very important raw material. When during the Second World War, it became impossible to obtain the bark from the Java’s plantations, researchers tried to figure out a strategy for its chemical synthesis (that was first achieved in 1944 6). Furthermore, efforts were made to obtain alternatives to quinine, and this led to the synthesis, among others, of chloroquine, hydroxychloroquine and mefloquine. These compounds are also used against malaria (5) and, some of them, in other few clinical conditions (e.g. rheumatoid arthritis, lupus, etc.).
However, they all have several side effects (5) and their mechanism of action against malaria is something still not completely understood. Even less understood (not to say unknown) is how they could help against COVID-19, although several hypotheses have been made, for example linked to the observed anti-inflammatory properties. Furthermore, hydroxychloroquine showed the ability to inhibit the virus replication in vitro. Therefore, these compounds are currently being tested in clinical trials both in the prophylaxis against SARS-CoV-2, in the treatment of some of the symptoms of COVID-19, as well as in the prevention of the onset of severe symptoms.
Unfortunately, severe side effects as well as ineffectiveness have been already reported in some cases. However, the clinical trials are still ongoing, and we need to wait to know more about the potential use of these drugs.
Please also notice that the compounds currently under study are not found in the Cinchona bark, since they are only obtained by chemical synthesis.
Colchicine
Colchicine is an alkaloid that was first isolated from Colchicum autumnale (autumn crocus, meadow saffron)f and it has been used so far in few instances, like to reduce pain and inflammation in patients experiencing acute attacks of gout, in the treatment of exacerbations of familial Mediterranean fever and of recurrent pericarditis (7,8). However, it is used only when other less harmful treatments do not work: this compound is highly toxic, as it interferes with very important structures within the cells, impairing key processes, above all, cell division.g Moreover, many other processes are disrupted, and the activity is not cell or organ specific, therefore it finally leads to multi-organ dysfunction and failure (8).
The rationale behind the trials testing the use of colchicine against COVID-19 is that it has shown anti-inflammatory activity.h It has also been proposed as a candidate in the reduction of myocardial injury in COVID-19 patients.
As for the previous group of molecules, this does not sound as the safest route to follow. However, once again it is important to wait for the trial outcomes.
More natural products on the way
One clinical trial is proposing the use of etoposide, an anticancer drug derived from podophyllotoxin (isolated from several species of Phodophyllum), to counteract the cytokine storm in COVID-19.i Finally, there is a clinical study proposing the use of tetrandrine, an alkaloid isolated from Stephania tetrandra (and other herbs), together with the standard therapy to act on the COVID-19 induced pneumonia.
Coming to the herbal remedies, we also already talked about the myths concerning them in the previous post. However, I also underlined how in few cases there is, to some extent, evidence of bioactivity. Moreover, some of them furnished chemicals that are also being tested right now, unfortunately at much earlier stages compared to the ones discussed before; we are talking indeed about in vitro studies. An example is artemisinin that is currently being studied by researchers of The Max Planck Institute of Colloids and Interfaces, together with medical researchers in Denmark and Germany, in laboratory cell studies against the novel coronavirus disease. Another example is glycyrrhizic acid, a compound derived from liquorice root. Both compounds showed activity against coronaviruses, but if they might help against SARS-CoV-2 is still under investigation.
A long way to go…
Unfortunately, despite the known effects on human health as well as the effectiveness as drugs of many herbal remedies and plant natural products, many of them are not mechanistically understood; we do not know yet how they really act. Maybe a much bigger effort should be done in this direction by researchers working on natural products.
I would like to underline also that the compounds listed before are everything but safe, therefore self-medication is never advisable, even when for any reason it is possible to have access to them. It is always a good idea to stick to official science and medicine, without following advices coming from other sources.
Finally, despite the big efforts that are also being made towards a therapeutic approach, we must keep in mind that vaccination is the most effective approach to control and ultimately eradicate infectious diseases.
Notes
a. Please notice that while the trials in the European registry are all approved studies, the ones in the NIH registry have not necessarily been approved.
b. Analogues are, in this case, compounds with similar structures, but differing in respect to certain components.
c. Quinine is also present in some drinks, but in very small amount.
d. Alkaloids are a specific class of natural products.
e. Yes, the same Louis Pasteur very popular for his discoveries in microbiology. He was also a chemist (and physicist, as well) and gave a great contribution also to this field. After graduating at the École Normale Supérieure, he was actually appointed Professor of Chemistry.
f. Afterwards, it has been isolated also from other sources.
g. In technical terms, colchicin binds to tubuline, disrupting the microtubular network and making the cell unable to form a functional mitotic spindle.
h. The hyper-inflammation seems to be one of the main problem in severe cases of COVID-19
i. Once again related to inflammation.
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