CSIR-IICB team develops first-in-class drug-like molecules with therapeutic potential for autoimmune and metabolic diseases
As the humanity gets into more and more urbanized life all over the world, a major shift in the dominant global diseases have occurred towards noncommunicable diseases, like diabetes, heart diseases, cancer and several autoimmune diseases like lupus, psoriasis and rheumatoid arthritis.
Autoimmune disease, where one’s immune system itself turns against one’s wellbeing, are less talked about in public spheres, although millions of people suffer from these silent killers worldwide and the therapeutic options are extremely limited in most if not all cases. A number of therapeutic targets are established in several autoimmune diseases. Perhaps most interesting are immune cell proteins called toll-like receptors or TLRs, which serve to recognize foreign elements on invading pathogens to mount an immune response to keep you healthy. A number of such TLRs have been found to get aberrantly activated in a number of autoimmune disorders as well. Thus inhibition of these receptors can be an important therapeutic strategy to be explored. Among the TLRs one specific TLR, TLR9 is implicated in a great majority of autoimmune diseases, e.g lupus, psoriasis, type 1 diabetes, Sjogren syndrome etc. In most of these diseases, the available therapeutic options are nonspecific suppression of the immune system with corticosteroids or other immunosuppressive drugs, because drugs specific for established therapeutic targets, like TLR9, are not available. Interestingly, a number of recent reports from all around the world have also implicated TLR9 in a number of metabolic diseases, like type 2 diabetes, fatty liver disease as well as atherosclerosis. Thus TLR9 are very exciting but yet unexplored therapeutic target in a number of very important clinical contexts, which constitute major disease burden globally.
Dr. Arindam Talukdar, who is an expert in pharmaceutical sciences and medicinal chemistry, took up this challenge of developing novel TLR9 inhibitors for clinical use when he joined as a scientist in CSIR-Indian Institute of Chemical Biology, Kolkata. He was joined by Dr. Dipyaman Ganguly, a clinician turned basic immunologist and currently running a laboratory in the same institution. Dr. Ganguly has a long-standing interest in understanding autoimmune disorders and his laboratory was involved in identifying the importance of TLR9 in several autoimmune and metabolic diseases. Now this team of scientists from CSIR-IICB has developed a library of molecules which are very specific inhibitors of human TLR9. These molecules are also found to have excellent properties for pitching them as candidates for clinical trials, e.g. on giving orally to animals these are nicely taken up by the body with therapeutic levels achieved in blood within hours. The CSIR-IICB team has acquired the intellectual property on this novel compendium of TLR9 inhibitors through patents in India as well as in several countries all around the globe.
According to Dr. Talukdar “This had been a rough ride given the limited infrastructure resources we had in a public-funded research institute, as compared to the multinational pharma giants who have dedicated team and pipelines for drug development. But our approach to the problem was very unique as we guided the gradual evolution of our successively synthesized molecules by their biological activity on the immune cells which was done by Dr. Ganguly’s laboratory”
A committed group of Ph.D. students were the key to this development process, notable among them are Barnali Pal, Swarnali Roy, Ayan Mukherjee and Biswajit Kundu from Dr. Talukdar’s laboratory and Oindrila Rahaman and Deblina Raychaudhuri from Dr. Ganguly’s laboratory. Dr. Ganguly feels that major achievement of this project has been motivating and working with young research fellows, who have never been trained to be on drug-development projects, which is starkly in contrast with the pharma industry which has the great support of highly skilled and specialized manpower apart from the huge funding they enjoy.
The future of these molecules depends on successfully crossing all the required steps of further validation in preclinical disease models, toxicity studies and finally clinical trials in humans, as with any other drug. These subsequent steps are significantly more expensive and involve several regulatory approvals and third party validations and can only be executed properly through established pipelines existing in the pharma industry. So the CSIR-IICB team, on encouragement from the Director of the institute Prof Samit Chattopadhyay, is looking forward to industrial partners who can take over the baton and take these molecules forward for clinical translation.
According to Prof. Chattopadhyay “This is a unique opportunity that CSIR-IICB has achieved through the hard work of this talented team of scientists whereby it can contribute to the nation in a big way as well as leave a mark in global drug research. But this will also depend on the right choice of partners who will respect the intellectual rights of our scientists and will enthusiastically move forward with the molecules into the further required steps”.