12 More on Chiral Drugs
This information is modified from an originally published article in The Conversation and is republished here under a Creative Commons license. The author of the original publication is Sajish Mathew, Assistant Professor of Drug Discovery and Biomedical Sciences, University of South Carolina.
The effects a drug or chemical compound have on the body depend on how its atoms are arranged in space. Some compounds have a dark twin with the same molecular formula but different 3D structure – and this can have consequences for what they do or don’t do in the body. Consider the tragic story of thalidomide, a morning sickness drug that caused thousands of birth defects and miscarriages. While one form, or isomer, of thalidomide has a sedative effect, the other is thought to cause abnormal physiological development. Because the two versions can convert back and forth in the body, it’s dangerous to take either form of thalidomide while pregnant.
The author’s research has focused on one such compound found in red grapes and peanuts, resveratrol. It has been a scientific mystery why clinical trials on using resveratrol to treat Alzheimer’s disease have had inconsistent results. Turns out, it may be because two different forms were used – while one may help with cognition and memory, the other may be toxic to the nervous system.
Amino acids, the building blocks of proteins, are chiral molecules. Living organisms primarily make proteins from amino acids with L configurations. The D configuration, however, has many other functions in nature. Bacteria, for example, use D configuration amino acids to make their cell walls. Mammals use D configuration amino acids as messengers in their nervous and endocrine systems. The amino acid tyrosine is one important exception to the L configuration rule. Unlike other amino acids, both the L and D configurations of tyrosine can be activated for protein synthesis by an enzyme called tyrosyl-tRNA synthetase (TyrRS). The presence of D-tyrosine can make it difficult for cells to synthesize proteins that only use L-tyrosine. However, cells have evolved enzymes that can discriminate between both versions and ensure that only L-tyrosine is used. When tyrosine-consuming enzymes are absent, the resulting increased levels of tyrosine in the body can have toxic effects, including damage to the nervous system. Recently published work from the author’s lab suggests a potential reason why too much tyrosine can be neurotoxic. When we added increasing amounts of L-tyrosine to rat brain cells in a petri dish, we found that it decreased levels of TyrRS, the enzyme that activates tyrosine to make proteins without causing damage to the body. Surprisingly, adding D-tyrosine not only caused TyrRS levels to drop, but also killed the neurons.
When the author’s group looked at the brains of Alzheimer’s patients who show increased tyrosine levels, they also found that TyrRS enzyme levels are depleted. Their hypothesis is that as tyrosine levels in the brain increase, TyrRS enzyme levels drop and cause damaging effects on the brains of those with Alzheimer’s. These findings indicate the potentially important role TyrRS may play in the synthesis of proteins essential for cognition and memory. These findings have implications for studies on resveratrol, a compound found in red wine that researchers have been examining for potential health benefits. While some clinical trials found that resveratrol can improve cognitive function in people with Alzheimer’s disease, others found it had the opposite effect and made the disease more severe. Why resveratrol can have such varying effects has remained a scientific enigma.
Resveratrol comes in two forms, cis-resveratrol and trans-resveratrol. The “cis-” and “trans-” prefixes, much like L- and D-, describe how the same atoms in two isomers are arranged differently in space. The two forms of resveratrol bind to TyrRS in different ways, they can result in opposite effects in neurons. While cis-resveratrol was able to increase TyrRS levels in rat neurons in a petri dish, high concentrations of trans-resveratrol depleted TyrRS and caused neural damage. However, low concentrations of trans-resveratrol can convert into cis-resveratrol in the body. This result leads to an increase in TyrRS levels and its associated benefits. Many clinical trials on resveratrol failed because none tested cis-resveratrol alone. We believe that this may also explain why trials that used high doses of trans-resveratrol saw harmful effects, while trials that used low doses of trans-resveratrol that were then converted into cis-resveratrol in the body saw beneficial effects.
Beyond the individual atoms and bonds of molecules, the body also cares about how they’re arranged in space. Paying attention to the different forms a drug takes could help lead to more effective treatments. Can we make enantiomers of drugs, instead of racemic mixtures, that are only biologically useful?
The following information is modified under the under a Creative Commons license. The author of the original article is Raman Rios, Associate Professor in Organic Chemistry, University of Southampton. The original article can be found here.
Benjamin List and David MacMillan, respectively based in Germany and the US, shared the 10 million Swedish kronor (£870,000) Nobel prize in chemistry 2021 for their development of “organocatalysis” – a precise tool for constructing molecules which has boosted pharmaceutical research and made chemistry greener and cheaper. Their research dates back to 2000, when the chemists independently developed the first steps of what today is called “asymmetric organocatalysis”, which is the activation of chemical reactions by small organic molecules. Many technologies and areas of research rely on molecules that have to be created in chemical reactions. These can, unfortunately, be very slow, which is why chemists often use catalysts – materials that speed up chemical reactions. Before the work of List and MacMillan, there were only two types of catalysts available: metals or enzymes. The duo’s most important achievement was spotting something that nobody believed possible: that small organic molecules such as amino acids could also work as catalysts. This discovery enabled the pair to create “asymmetric reactions”. In chemical reactions, many molecules are produced as racemates. This is annoying when you only want one of them, which is often the case in the pharmaceutical industry. In fact, this is what went wrong with the drug thalidomide.The beauty of organocatalysis is that you can produce a specific molecule without its mirror cousin. The possibility of avoiding using metals as catalysts in chemical reactions has also made it easier for pharmaceutical companies to purify compounds. This is an important final step in the manufacturing of pharmaceuticals, and involves the removal of dangerous chemicals, including certain metal catalysts. Another major improvement of organocatalysis compared with other types of catalysis is that it is easy to carry out: you can do it at room temperature under simple conditions. It is also easier to reliably predict and control the outcomes than it is with other types of catalysis. What’s more, metal catalysts such as palladium or rhodium can be expensive. An extremely beautiful example of a cheaper alternative is proline, a simple amino acid that is often used as an organocatalyst, which is so efficient that it has entirely substituted certain expensive and complex metal catalysts.
Organocatalysis isn’t only a cheaper alternative, it is also more environmentally friendly, typically containing common and abundant elements such as oxygen, nitrogen, sulphur or phosphorus rather than iridium or palladium. List and MacMillan soon became the leaders of this pioneering new chemistry, developing more and more reactions and catalysts, and envisioning new ways of expanding the field. One of the most important aspects of this work was how readily it changed the attitudes of so many organic chemists, who turned their attention to organocatalysis and embraced it. This meant that chemists in many different areas of research were able to synthesize complex molecules in great specificity, which made the field grow exponentially.
