Dr. Choong Meng Ling’s one-north Festival talk in 2017, he talked about how most of the medicine we take everyday, like Panadol and runny nose medicine, are small compounds that act like arrows to target proteins in our body that are causing disease. Here, we follow up and ask Choong for more insights on some of the questions you may have had after listening to his talk.
Q1. You mentioned in your talk that targets for disease treatments are proteins and medicines are arrows that target those proteins. Are proteins the only things that medicines can target in order to treat disease? Or are they just the easiest targets?
Our cells are made up of proteins, carbohydrates and lipids. Carbohydrates and lipids are usually the product of an enzyme (which is a protein) or they are modified by a protein. It is usually a malfunctioned protein that leads to an aberrant carbohydrate or lipid causing a disease in our body. For example: Glycogen storage diseases are due to inability to process glycogen and glucose, Niemann-Pick disease is due to accumulation of certain lipids in the nerve and immune cells, etc. Proteins are also the machines that catalyse the metabolic reactions in our bodies (e.g. in burning fat and sugar), transport molecules (e.g. haemoglobin in our blood, which transports oxygen, is a protein), defend against invading microorganisms, and transmit messages from cell to cell. Hence, targeting the protein will stop the disease in its track.
Unlike carbohydrates and lipids, each type of protein has a unique three dimensional shape. The unique shapes of the proteins contribute to the diverse functions mentioned above. The unique shapes of the proteins also allow scientists to make specific medicines to target them with minimal “cross-effect” to another protein. This is the “lock and key” analogy used in the talk. Depending on the location of the protein in a cell, proteins can be targeted for disease treatment using small molecules, antibodies and hormones.
Proteins are not the only target for disease treatment. DNA is also a popular target for disease treatment. However, unlike proteins, DNA cannot be targeted with small molecules. This is because genes, which are made up of DNA, lack unique three dimensional structures that differentiate one gene from another, so it’s not possible to target a gene by its shape. Scientists, however, managed to overcome this problem by exploiting the ability of the subunits of DNA (known as pentose sugars) to pair uniquely with each other. Scientists make short DNA fragments that pair with a gene and disrupt its function.
Q2. There are different types of compounds that can be used to target proteins. In the talk, you also mentioned things like hormones, antibodies and cell therapy. Why are small molecules the most common way to treat disease?
Small molecule drugs account for about 90% of the therapeutics in today’s pharmaceutical market. Compared to treatment of diseases with hormones, antibodies and cell therapy, treatment using small molecules is more common because:
- Most diseases happen inside our cells, which giant molecules like antibodies cannot penetrate. Small molecules are engineered to be able to enter cells easily.
- Our body may generate immune response against hormones, antibodies and cells used for therapy. Our body does not generate immune response towards small molecules
- Small molecules are cheaper and easier to manufacture compared to hormones, antibodies or cells for cell therapy.
- Most small molecules are easier to administer because they can be made into tablets or pills, which the patient can take on their own.
- Unlike antibodies, hormones and cell therapies, tablets and pills last longer and can be stored at room temperature on the shelf, lowering operating costs for the manufacturer.
All these reasons combined to make small molecules a popular choice for treating diseases.
Q3. You said you work from a library that has half a million compounds to be tested. Who came up with this library, and how? Also, do you ever fear that you will miss out on finding the right compound because it’s just not in your library?
ETC has a collection of about half a million small molecules (compounds) with diverse structures. These small molecules are purchased from commercial sources, from companies that specialise in making small molecules with all kind of shapes and structures. In ETC, our chemists filter through commercial databases using special algorithms to select for compounds with diverse structures before we purchase them. Our chemists also make compounds with drug-like structures that are unique to ETC. In this way, we ensure that we have a diverse collection.
High throughput drug screening is basically a brute-force approach. The more compounds you screen, the higher your chance of finding a suitable candidate for your target protein. However, high throughput drug screening is also capital- and labour-intensive. We need to find a balance in performing sufficient screens while keeping the cost low. Three years ago, we performed a screen using similar methods as reported by a pharmaceutical giant. We screened just 250,000 of our compounds and we found hits that are similar to what the pharma giant found after screening 3 million compounds. Hence, we are reasonably confident that we are on par with pharmaceutical companies with much larger compound collections!
Q4: Many of your lab’s recent breakthroughs have been related to cancer treatments, (or at least the ones detailed in your talk!) When you begin a project, how do you identify targets of interest, and what factors go into it?
In ETC, we have built our expertise around cancer and infectious disease. Our targets of interest come from our collaborators. We also venture into other disease areas if we can partner with collaborators with suitable targets.
Picture a city map in your mind. There are many roads that can lead to a particular destination. Our cells contain very comprehensive metabolic and signaling pathways that could rival the traffic systems in the largest city in the world. It is not an easy job to identify a protein that is crucial for the development of a particular disease. Hence, we actively seek to partner with scientists who are very experienced in a disease pathway, who know these maps very well. The scientist will be able to tell us which cellular signaling pathway is causing a particular disease and which protein in that pathway is most critical to the disease development. We will work with the scientist to develop assays to verify the importance of that protein and to miniaturise the assay so that we can use it for high throughput drug screening.
As I have mentioned in my talk, the hits that we find after the high throughput screening are not the end of the story. Our medicinal chemists, biochemists, biophysicists and preclinical pharmacologists will come in to modify the hit to make it more potent for stopping the disease, reducing non-specificity (side effects), and to make it more absorbable by our body. This is a crucial drug development step that most academic scientists do not have the expertise to carry forward. This is where ETC compliments the academics and bridges the gap from basic science to drugs in clinic. The activities carried out in ETC to improve the efficacy of the drugs also modifies the hits (which are commercial compounds that we purchased) into unique compounds that we can patent. We will be able to generate revenue when we license or sell the drug to a pharmaceutical company. Thus, ETC helps to transform basic academic research into economic benefits for Singapore.