Discovery of New Drugs from Natural Products
Natural products are functional metabolic products produced by organisms in nature during the process of evolution to adapt to the environment, compete against antagonists, communicate, resist external invasion, and transmit signals. They mainly include components or metabolites found within animals, plants, insects, marine organisms, and microorganisms, as well as many endogenous chemical components found within humans and animals. Compared to synthetic compounds, natural products exhibit a greater diversity of skeletal types, richer functional groups, and more complex stereochemistries. The unique structures endowed by natural products confer them with unique biological properties. Therefore, natural products have always been important research subjects in the field of life sciences and significant sources for drug discovery.
Drugs from Natural Products
In the 1960s, at the request of Vietnam, China mobilized its national efforts to research new antimalarial drugs. Researchers extensively studied hundreds of single and compound traditional Chinese herbal medicines mentioned in ancient medical texts. Artemisinin was found to have a high frequency of antimalarial activity during these studies, leading researchers to focus on the ethanol extract of Artemisia annua. Later, Chinese scientist Tu Youyou altered the extraction method, isolating artemisinin from Artemisia annua using ether and confirming its antimalarial activity. Its structure was ultimately confirmed through spectral behavior analysis, X-ray crystallography, optical rotation dispersion analysis, chemical reaction verification, and total synthesis. Due to its inherent poor bioavailability and pharmacokinetic properties, the application of artemisinin has been limited. To address this issue, researchers have optimized the structure based on artemisinin as a lead compound, developing several new drugs such as artemether, dihydroartemisinin, and arteether. These drugs have been widely used globally and occupy a central position in antimalarial therapy.
Canagliflozin - Hypoglycemic Drugs
In the early 1980s, researchers discovered that phlorizins with dihydrochalcone as the glycosyl moiety had dual activity in inhibiting the sodium-glucose cotransporter 1 and 2 (SGLT1/SGLT2). Selectively inhibiting SGLT2 without affecting SGLT1 was identified as a new approach for treating type 2 diabetes, as it does not interfere with glucose absorption in the gastrointestinal tract or the insulin system. Researchers used root glucosides as lead compounds for structural modification, aiming to obtain a drug with high selectivity for SGLT2, metabolic stability, and a novel structure. It was first determined that the connection between the sugar moiety and two benzene rings was essential. Subsequently, investigation into the length of the connecting chain between the two benzene rings led to the identification of compound 2 with higher selectivity. To improve compound stability, the O-glycoside was replaced with a C-glycoside, allowing the sugar moiety to be directly connected to the glycosyl moiety via a C-C bond to obtain compound 3. Finally, bioelectronically and other substitutions were made to the two benzene rings, resulting in canagliflozin. Canagliflozin was approved by the US FDA in 2013 for the treatment of type 2 diabetes.
Lipid-lowering Drug - Lovastatin
Initially, the association between cholesterol and coronary heart disease was discovered, revealing that coronary heart disease is caused by low-density lipoprotein (LDL) cholesterol. Lowering LDL cholesterol in the bloodstream is expected to prevent and treat cardiovascular diseases such as atherosclerosis, myocardial infarction, and coronary heart disease. 30% of cholesterol in the human body is obtained from external intake, while 70% is synthesized by the body itself through multiple enzyme-catalyzed reactions from acetyl-CoA. Intervening in different stages of the enzyme system holds the promise of inhibiting cholesterol biosynthesis. HMG-CoA reductase is the rate-limiting enzyme in cholesterol synthesis. Inhibiting this enzyme can block cholesterol synthesis, and its upstream substrate can be metabolized and decomposed by alternative pathways, thus not accumulating in the body and causing adverse reactions. Therefore, this enzyme is an ideal target for developing cholesterol-lowering drugs. Biologists discovered that fungi's cell walls contain ergosterol instead of cholesterol, indicating that fungi may produce substances that inhibit cholesterol synthesis. Based on this, lovastatin was discovered. In 1978, Merck & Co. discovered lovastatin, which has a chemical structure similar to that of mevastatin, except for an additional methyl group on the ring. Lovastatin was approved by the US FDA in 1987 for the treatment of hypercholesterolemia. Subsequently, many other statin drugs were developed based on this, such as Pfizer's atorvastatin and AstraZeneca's rosuvastatin.
Antithrombotic Drug - Vorapaxar
Total synthesis studies of the natural product Himbacine, construction of key intermediates and parallel synthesis of Himbacine and its analogs. Himbacine was initially studied in search of anti-Alzheimer's disease drugs, a selective antagonist of the acetylcholine muscarinic receptor M2 receptor, and then shifted to the development of PAR-1 inhibitors after randomized screening. During the universal screening of Himbacine and its analogues, researchers found that compound 4, in which the pyridine ring replaces the saturated nitrogen-containing six-membered ring and changes the substituent group on the ring with opposite chiral centers, has better PAR-1 inhibitory activity, but it is a CYP enzyme inducer that is readily metabolized in vivo, and it also suffers from drug-drug interaction problems. In order to overcome the pharmacokinetic problems of Himbacine analogs and to verify the presence of metabolic activity, their metabolites were investigated and another class of Himbacine analogs with similar activity but better pharmacokinetic properties was found. This compound had good efficacy in vitro and in vivo, but it was inactivated in vivo by rapid metabolism to dihydroxyl compounds, and in order to prevent oxidative metabolism at this site, a multi-substituent transformation study was performed at this site, which ultimately led to vorapaxar. Vorapaxar was approved for marketing by the FDA in 2014 for use in patients who have suffered a heart attack or blocked arteries to reduce the risk of death from further heart attacks, strokes, etc.
In addition, there are also other drugs discovered from natural products, such as the anti-tumor drug Eribulin derived from Halichondrin B, and the anti-diabetic drug Dimethylbiguanide developed from guanidine.
Strategies for Natural Product Drug Discovery
Evaluating the effects of compounds in natural products through genomics, transcriptomics, proteomics and metabolomics allows for rapid and effective screening of compounds. This leads to better drug candidates.
- Role of Genomics in Natural Product Drug Discovery
Genomics can help target natural products in the drug discovery process in a number of ways. Certain cell signaling and enzymes target specific compounds for metabolism, which can be achieved through genomic analysis. Several genome-based approaches, including sequencing and transcriptomics studies, have allowed the evaluation of many systems in terms of compound targeting. For example, protein modifications, binding sites for transcription factors, methylation patterns, and DNA structural alterations are being evaluated at the genomic level.
- Role of Proteomics in Natural Product Drug Discovery
Proteomics analysis has emerged as a complementary approach to genomics and transcriptomics methods for identifying and characterizing the mechanism of action of many natural products. From protein expression, function, and biosynthetic cascades, proteomics can also translate to the quality of the natural products under review. Advances in mass spectrometry, including the use of isotopic labeling and in conjunction with two-dimensional (2D) electrophoresis, can reveal protein profiles associated with natural products in a manner similar to genomic data.
- Role of Metabolomics in Natural Product Drug Discovery
Characterizing the metabolomics of natural products is one way to identify and quantify the metabolites associated with a particular natural product. On the other hand, metabolomics is a way to measure the overall and changing metabolic changes in an organism tends to reveal more details about the natural product, its biological mechanism of action and its impact on the whole organism. Several well-established techniques including the use of NMR, mass spectrometry and UPLC to analyze natural products, especially ultra high performance liquid chromatography-TOF MS (UPLC-MS), have been used for metabolomics analysis of natural products, which has led to the revelation of new compounds with therapeutic effects.
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