Indian scientist's artificial enzymes may help treat heart disease

Nano molecules that may help treat cardiovascular diseases, one of the top killers in India, as well as conditions such as hypertension are being synthesised in a Bengaluru lab under the watchful eye of an Indian scientist.

Professor G Mugesh and his team at the Indian Institute of Science are working on synthetic molecules such as artificial enzymes, which may help develop novel ways to tackle cardiovascular disorders, including heart attacks.

"What we do is, we synthesise these compounds in a chemistry lab, and study them for biological applications, particularly keeping in consideration their potential use in some major diseases," Mugesh said.

Endothelial dysfunction, a risk factor for plaque build-up inside arteries, and hypertension are also on the list of cures.

The team started with basic research on cellular studies in the lab, and is now planning to carry out animal studies.

Their research on the biological properties of novel small molecules and nanomaterial for use in biomedical research is the subject of global attention.

According to a study in The Lancet journal in August 2018, India accounts for about a fifth of cardiovascular deaths globally.

Cardiovascular diseases caused more than 2.1 million deaths in India in 2015 at all ages, or more than a quarter of all deaths, the Lancet study found.

The new molecules created by Mugesh and his team functionally mimic some key enzymes which do not work properly under diseased conditions.

Enzymes are molecules which significantly speed up the rate of almost all chemical reactions that take place within the cells. Biological molecules -- typically proteins -- are vital for life and serve important functions in the body, such as in cardiovascular system, digestion and metabolism.

"Our idea is basically to substitute the function of these enzymes with that of artificial enzymes. Artificial enzymes include nanomaterial that function as enzymes. These are emerging as a new type of compounds that exactly mimic the function of the natural enzymes in the human cells," Mugesh explained.

Mugesh, who works in the field of chemical biology -- an interface of chemistry and biology -- was on November 7 awarded the $100,000 Infosys Prize 2019 in Physical Sciences for his seminal work in the chemical synthesis of small molecules and nanomaterial for biomedical applications.

"We are in the 11th year of the Infosys Science Prize and we have more than 60 awardees, whom we have recognised, and many of them have gone on to do bigger and better things, e.g. two people won the Nobel prize this year -- professor Abhijit Banerjee and Esther Duflo, S D Shibulal," president of the Infosys Science Foundation (ISF), said.

Mugesh has worked on the design and synthesis of small molecules that functionally mimic enzymes containing selenium atoms, called selenoenzymes -- which protect cell components against oxidative stress -- in mammalian cells.

Oxidative stress is a disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses.

The researchers are focusing on the disorders which occur due to the change in the redox state -- gaining and losing of electrons by important chemicals in the cell.

"What we are trying to address is that can we bring these abnormal cells to the normal physiological state. Because when these redox changes happen, the physiological process of the cell becomes pathological. That's where we are testing these molecules," he explained.

While looking for enzymes to treat cardiovascular diseases, the team is targeting the redox regulation pathway, which involves enzymes such as superoxidase dismutase', and glutathione peroxidase', both of which play important roles in cardiovascular health.

While superoxidase dismutase' controls the formation of superoxides -- which cause oxidation of important chemicals in the cell glutathione peroxidase' regulates the levels of hydrogen peroxide, which is a signalling molecule.

Signalling molecules help in the communication process that governs basic activities of cells.

"What we feel is that the initial leads that we have got are very encouraging. We will certainly consider taking the research to the next level," Mugesh said.

Mugesh's recent research is aimed at the use of halogen bonding or bonds in elements such as chlorine and iodine, as a strategy to efficiently deliver proteins and synthetic small molecules into human cells.

Cellular delivery of proteins and small molecules is a major challenge in drug discovery and biomedical research, and Mugesh's strategy to use the halogen bond-mediated cellular uptake paves the way for the efficient delivery of therapeutic proteins and small molecule drugs into human cells.

In cellular experiments, researchers were able to increase the cellular uptake of the molecules by up to 95-98 per cent by introducing an iodine atom into these molecules.

"When we make new molecules and new enzymes, basically it is important that these molecules enter the cells. Otherwise it is difficult for us to go ahead with the drug discovery process," he said.

"To show the desired effects inside the cells, we found that our compounds are able to cross cell membranes," said Mugesh, a postdoctoral fellow at The Scripps Research Institute in California before taking up his current post in Bengaluru.

Mugesh noted that human trials can be done in the future depending on the outcomes of the animal studies.

Drug discovery, he said, is a multi-stage process which takes at least 10-15 years to get into human clinical trials.