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Reader: The new crown epidemic has swept the world, why hasn’t humans developed broad-spectrum and highly effective antiviral drugs like developing antibiotics?
Lao Liang: Before answering this question, let us clarify the definition of "broad spectrum".
broad-spectrum antibiotics are well known. Traditionally, it refers to antibiotics that act on two main bacterial categories, Gram-positive and Gram-negative. Now it generally refers to antibiotics that kill or inhibit the bacteria that cause diseases. Many antibiotics we are familiar with, such as early penicillin, later carbapenem and cephalosporin, are all broad-spectrum antibiotics.
broad-spectrum antiviral drugs, which people don’t seem to know very well, and some people have not even heard of, which is not surprising. Broad-spectrum antiviral drugs are also known, which refer to drugs that can inhibit the invasion and replication of multiple viruses. There are indeed not many broad-spectrum antiviral drugs. Ribavirin, which was launched in 1986, can be considered one, which can be used to treat RSV (respiratory fusion virus) infection, hepatitis C and some viral hemorrhagic fever .
It was because Fleming accidentally discovered penicillin at that time. He did not know its mechanism of action, but it had a very broad-spectrum bactericidal effect, so he achieved great success. Later, the mechanism was clarified. It acts on the cell wall of bacteria, inhibiting the synthesis of peptidoglycan (peptidoglycan). Many bacteria have the same synthetic pathway, while mammals, including humans, only have cell membranes and no cell walls. Therefore, penicillin can kill many bacteria, but it is basically harmless to humans and animals. With this precedent in
, the subsequent development of antibiotics will be compared with penicillin. If an antibiotic is not a broad spectrum but targets a particular bacteria, although there is also demand, its market will not be large. Multinational companies that pursue "blockbuster" drugs will stay away from it and leave it to small companies that survive in the cracks.
In turn, the earliest experimental antiviral drugs were developed in the 1960s to treat herpes virus infection. At that time, they were not known about their mechanism of action, but discovered through traditional trial and error methods. By the 1980s, when the genetic sequence of the virus was gradually unveiled, researchers began to understand the principles of virus invasion and replication and began to consider how to block these processes. So, we have antiviral protease inhibitors, polymerase inhibitors, and so on. They are all developed for proteins targeting a certain virus, and the specificity of the drug is very good (bad things are eliminated) and will not have much cross-activity.
market demand
Isn’t pharmaceutical companies want to develop broad-spectrum antiviral drugs? Of course not, because the market demand for broad-spectrum antiviral drugs is obviously huge.
Take our current COVID-19 epidemic as an example. Special effects drugs cannot be prepared in advance, and it is definitely too late to develop them again. However, if any pharmaceutical company has a broad-spectrum antiviral drug that has a significant inhibitory effect on the new coronavirus, it will not cause such huge losses to the epidemic, and the secondary disasters caused by this will not be so serious.
In this case, society will definitely have a very generous return to this pharmaceutical company. We believe Mr. Merck's famous saying: "We should never forget that pharmaceuticals are for patients rather than for profits. Profits come with them. If we remember this, it will never fail; the clearer we remember, the more it will come." If a company hoards and tries to make huge profits; or which country's government uses this as a bargaining chip to try to achieve certain political goals, it will definitely be despised by all mankind. How to cut into
?
Since there is a huge market, why don’t pharmaceutical companies invest heavily and work hard to develop broad-spectrum antiviral drugs? The main reason is that there is no good entry point.
Take protease , one of the main targets of antivirals.If you concentrate all the proteases of known viruses and go to the DEL of WuXi AppTe for a screening, I think some signs of compounds that have certain inhibitory effects on these proteases. starts with these compounds. Is it possible for scientists to develop the "pan- inhibitor " of viral protease? Although it is relatively difficult, there should be hope.
The problem is that proteases are not unique to viruses. There are also many proteases in the human body, which are very important for normal human functions. Therefore, scientists must also find all known human proteases and then perform counter-screening to remove the compounds among these "pan-inhibitors" that also have inhibitory activities on human proteases to ensure that the compounds we selected are "pan-non-inhibitors" for human proteases, and there are not many compounds left.
So why is ribavirin mentioned at the beginning of this article effective against several viruses? The mechanism of action of ribavirin is not yet clear. Studies have shown that ribavirin is the mutation source (Mutagen) of the RNA virus. Once the RNA of the virus is embedded in the polymerase , the new copy of the virus will be inactive. But the human body also has RNA and polymerase, and cannot withstand fatal mutations. Therefore, its "broad spectrum" is very limited. Where is the hope for
?
If one day, scientists discovered a biological process common to most viruses, but it does not exist in humans and animals, many pharmaceutical companies will become interested in finding ways to block this process. Perhaps in the soil under our feet, some microorganisms have "developed" broad-spectrum anti-viral "chemical weapons" for their own survival, waiting for a prepared person to discover it by chance.
In June 2020, in New Jersey, USA, Guibai worked at the Merck New Drug Research Institute for many years, devoted himself to medicinal chemistry , and made great achievements. A few years ago, he returned to China to join WuXi AppTec, engaged in business development, project management and operations in the United States. Dr. Liang is the author of the book "The Story of New Drugs". With long-term accumulation, unique perspective and vivid text, he told the "Stories Behind the Development of New Drugs" through the "Lao Liang Talks about Medicine" column, which is refreshing and enigmatic. Dr. Liang Guibai is currently the co-founder and chief scientist of Kaiyi Pharmaceutical. Readers are welcome to contact Dr. Liang via email [email protected].
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