Perfectionism on part of proteins in cargo delivery could save lives

August 2015

A minor fault in any member of the team of proteins carrying structural elements for melanin pigment maturation could deprive us of not just our colour, but could be fatal when combined with few other factors.

Trucks and lorries rule the world of cargo delivery. Any malfunction in them affects the timely delivery of the cargo at the destination and where and how they are used in the further processes. This chain of events is not very different at a cellular level. Our cells also have their own transport pathways responsible for the cargo delivery at the right destination at the right time. Any variations to that system shows up as symptoms to fatal diseases. Dr. Subba Rao and team from the Indian Institute of Science, Bangalore, unravel the nitty gritties of one such transport pathway in animal cells where failure to deliver the cargo, in this case melanin synthesizing enzymes, could result in fatalities.

Melanin pigments are responsible for the colour of our skin and also play an important role in protection against radiations and any other damage from light. Melanin pigment is produced in cellular organelles called melanosomes which need melanin synthesizing enzymes transported from other organelles. The enzymes transported into premature melanosomes facilitate the maturation into fully pigmented melanosomes. The transport pathway is completed with the help of four multi subunit protein complexes, BLOC 1, 2, 3 and Adaptor protein 3 complex.

BLOC 1 consists of 8 subunits, functioning in the upstream of the pathway while BLOC 2, a 3-subunit protein complex, functions towards the end of the pathway in directing the transfer of molecules towards maturing melanosomes for subsequent reactions. It does so by the specific method of “tethering” or by stabilizing the intermediate molecules that need to be transported.

Mutations in BLOC 1 or BLOC 2 proteins result in inefficient delivery of melanin synthesizing proteins to melanosomes and thus failure in full expression of the melanin pigment. This malfunction manifests in the form of albinism of skin, ear and eye, also referred to as oculocutaneous albinism. This is one of the primary symptoms in Hermansky-Pudlak Syndrome (HPS). The other symptoms are lung infections, which are mistaken as Tuberculosis in most cases in India. Both the lung pathology and albinism put together result in HPS but the confirmatory diagnosis is genetic sequencing of the patient and the parents. HPS generally shows up in children within the age group of 4-6. Out of the 16 possible genetic mutations that can result in HPS, only 9 are known so far. Three out of those nine subtypes are a result of mutations to the BLOC 2 protein.

Even though BLOC 1 and 2 play their respective roles in the overall transport pathway, their molecular functions are not yet clear. There are additional proteins that are responsible for membrane trafficking throughout the cell in most transport pathways. These proteins are called Soluble NSF (N-ethylmaleimide sensitive fusion proteins) Attachment Protein REceptor (SNARE). SNARE proteins, a family of about 60 proteins has been known for their role in membrane fusion during transfer of information. For the first time, the team from IISc has identified two members from the SNARE family that are involved in the transport pathway to melanosome. Immortal melanocyte cell lines from mice, both wild type and mutated, were used for the experiments. The expression of these cell lines were estimated by their absorbance at certain wavelengths and compared with levels of protein expressions found in healthy cells. The team concluded that not only do SNAREs play a vital role in the endosome and melanosome membrane trafficking but are also responsible for maintaining the melanosomal proteins in their stable states until delivered to the maturing melanosomes. Very strong interactions between the SNARE proteins and BLOC 1 has been reported in the initial steps of the transport pathway.

Dr. Subba Rao and team intends to further work on uncovering the details of the interactions between the SNAREs and BLOC 1 and 2 complexes. It is important to understand the specific roles that BLOC 2 plays in the cell and would help in filling the gaps in the transport pathway. How and what delivers the cargo at the destination is yet to be understood. Whether the membranes actually fuse for the transport of the proteins or only the proximity of molecules with the opposite membrane to the surface completes the transport? What are the guiding proteins? If the SNAREs go back to their respective states after the transfer is completed? These are few questions the team is looking forward to resolve in their future research.


Keeping DNA in good shape

December 1, 2014

A stitch in time saves nine, goes the old saying. And here a team of scientists at Indian Institute of Science study RAGs (recombination activating genes) to understand the stitching and unstitching of the DNA, which in certain ways leads to genomic instability and cancer.

The RAG complex consists of two genes, RAG1 and RAG2. These genes produce the RAG proteins – RAG1 and RAG2 — which are expressed in the B and T cells of our immune system. The B and T cells help in locating and dealing with foreign substances that enter our bodies like bacteria and other microbes. The cells can recognise foreign bodies using proteins on their surfaces. The RAG gene complex helps in the generation of these surface proteins.

The high number of surface proteins that need to be produced sometimes leads to genomic instability and “chromosomal translocations” – rearrangement of bits of the chromosome, which can lead to incorrect arrangement of genes. This can lead to diseases like lymphoma and leukemia.

In a previous study, Dr. Sathees C Raghavan and Rupa Kumari showed that RAG proteins cleave DNA when they spot a particular sequence of nucleotides. In this paper, they have focussed on studying the factors that can regulate DNA cleavage efficiency of the RAG proteins. This can improve our understanding of how the DNA cleaving activity of these genes is turned on and off.

They found that apart from the sequence of a particular DNA complex, the sequence of the regions surrounding it are important in determining where the RAG proteins bind and where they cleave. The presence of cytosine and thymine in a single stranded region of the DNA complex dictates the position of nicking. A minimum of two cytosines are required for the RAGs cleavage efficiency. The deletion of certain sequences could result in the loss of sequence specific nuclease activity of RAG but it retains its structure specific nuclease activity.

The further understanding of these factors which regulate the stability of the above mentioned DNA complex could help us decipher the mutations that act as the root causes leading to cancers like lymphoma and leukemia.

The paper has been published online on 14th November in The FEBS Journal.

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A biosensor to peer into the insides of a HIV infected cell

December 8, 2014

One of the unique features of the AIDS virus, HIV-1, is that it can exist inside human cells for years without causing any harm. It then reactivates to cause infection when conditions are suitable. Researchers from IISc, Bangalore, the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi and Jamia Millia Islamia, New Delhi have exploited a non-invasive biosensor that can measure what is going on within HIV-1 infected cells in real-time.

This technology can offer insights which can help in controlling the AIDS infection and also provide insight on the interactions between HIV-1 and the tuberculosis causing bacteria, Mycobacterium tuberculosis (Mtb),within the cells.

Acquired Immune Deficiency Syndrome or AIDS is a devastating disease, which is unfortunately quite common. Since its discovery, AIDS has caused an estimated 36 million deaths worldwide (as of 2012). Its causative agent, the Human Immunodeficiency Virus (HIV), has thus been a hot topic of research.

Our body produces oxygen free radicals called Reactive Oxygen Species or ROS, during routine cellular metabolism. When not regulated properly, accumulation of these ROS can lead to oxidative stress. Heightened oxidative stress is one of the primary causes of reactivation of HIV-1 in infected cells.

Oxidative stress also decreases proliferation of disease fighting immune cells; besides, it causes loss of memory in immune cells. These factors reduce the efficiency of the immune response toward the HIV. A major cellular antioxidant called glutathione (GSH) functions as a protective shield against the oxidative stress. GSH levels in infected cells and tissues are indicators of the level of infection.

The team has devised a non-invasive biosensor methodology for precise measurements of GSH levels within HIV-1 infected cells. Earlier methods use whole cell or tissue extracts, which destroy detailed information related to the GSH levels in different areas within an infected cell. Study discovered that a modest increase in oxidative stress is sufficient to reactivate virus from latency. This may allow researchers to adopt a “shock-and-kill” strategy in which virus could be reactivated by oxidative stress inducing compounds and subsequently killed/flushed by current anti-HIV drugs. The fluctuation of GSH levels detected by the biosensor also helps understand the expression of antioxidant genes and related pathways during latent and active stages of infection.

The sensitivity and specificity of this biosensor could be further used in understanding the physiological changes in HIV-1 infected cells and the mechanism of drug action.

“Importantly, we also discovered that Mycobacterium tuberculosis, another major human pathogen, specifically disturbs glutathione balance to increase the replication of HIV. Since TB is the major cause of HIV related deaths, our findings have major mechanistic and therapeutic potential for both TB and AIDS (among the main causes of human death)”, said Dr. Singh.

The paper appeared in The Journal of Bilogical Chemistry on 18th November. DOI: 10.1074/jbc.M114.588913

Taking help from ageing cells to suppress tumours

December 8, 2014

As cells grow older, their DNA gets damaged. Depending on the extent of damage, the cell can repair the DNA and continue its life, or self destruct and die. A molecule called ATM kinase is involved in this decision making process.

Deepak Saini’s lab at IISc has delineated the role of ATM kinase in this important process. The extent of DNA damage either triggers activation of cancer causing genes, or deactivation of tumour suppressor genes. Both these processes can initiate uncontrollable multiplication of cells, leading to cancer. The other possible outcome of DNA damage, especially if very severe, is cell death. The decision of the cell’s fate lies in the hands of the genetic errors accumulated. If the errors cannot be repaired, or can be detrimental if left unrepaired, the cells enter cellular senescence, which is basically ageing. Cell function deteriorates and ageing of the organism is the inevitable result.

The senescent condition of the cells depend on their respective abilities to maintain a persistent DNA damage state without inducing death or repair. There are a number of molecules like ATM kinase and ROS (reactive oxygen species) that play a critical role in regulating cell fate after the genomic damage.

Cellular senescence can be divided into two distinct phases – initiation or early senescence and the maintenance of senescence. The present research delineates the roles of ATM kinase in the initiation of senescence and importance of ROS in maintaining senescence. ATM kinase is one of the key proteins which decides the fate of a cell; it also acts as a quantitative sensor for DNA damage. When DNA damage is not so severe, the cell repairs its DNA and continues growth; in severe damaged states, the cell dies.

In the intermediate stages of damage, the cell enters the senescent stage activated by ATM kinase. “Our studies show that senescence or aging is one of the cell fates in response to DNA damage and the decision is dependent on the dose of damage and ATM kinase protein. Aged cells generate free radicals which is critical in maintaining their status quo”, said Dr. Saini.

Since the other two alternatives after DNA damage – death and cancer – are obviously harmful, a possible way to push a cell toward senescence instead of the other options can have possible therapeutic value. Cell senescence can be induced in tumour and cancer cells by using a sub-lethal dose of stress, by agents like gamma rays, hydrogen peroxide etc. which triggers the DNA damage response leading to senescence. Further research on this could help us devise a very simple yet attractive tumour suppressing mechanism.

The paper will be published in the Journal of Cell Science and appeared online on 21st November.

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Learning from insect social networks

October 20, 2014

Insects like honeybees and ants live in groups that constantly communicate with each other. In fact, communication networks in some insect groups have been successfully compared to artificial technological information transfer networks. Drawing parallels between such highly coordinated processes in living organisms and their artificial counterparts, a team of scientists from IISc, IISER-Kolkatta and BITS-Pilani, seek a better understanding of network communication, to improve the existing information processing networks.

The survival of living organisms depend on the well-coordinated processes at different levels – the cellular and genetic levels, for example. Group living animals take coordination to a different level — schools of fish and flocks of birds rely on competent communication by every individual to all other members, at every point in time. Efficient transfer of information happens through communication systems, which hold good even when there are time or energy constraints.

Among non-human living beings, social insects like bees have some of the most complex societies. Scientists study them to understand communication between the members of a colony, which ensures division of labour between thousands of individuals. Different species of social insects have different modes of communication: bees in large colonies communicate using chemical cues or pheromones, while wasps in smaller colonies use direct physical interactions.

Anjan Nandi and colleagues have studied a tropical wasp Ropalidia marginata to understand the flow of information within a colony. They found that the flow of information between individuals is by pairwise physical interactions, like dominance behaviour, which plays a major role in the regulation of activities of the workers in a colony. For example, foragers that find food receive more dominance over the non foragers, and the extent of dominance varies depending on the circumstances (higher during starvation while lesser during excess food). Apart from dominance, wasps also use paired behaviours like grooming, soliciting and food sharing for flow of information.

There are also global structures that emerge from the two way interactions: the average path length for communication and the average density of interactions could be determined from individual interactions. In other words, the building blocks of a network formation is identified by studying the local structural elements.

The analysis revealed that networks constructed from dominance behaviour in Ropalidia marginata is structurally similar to different biological and technological regulatory networks. Further, the networks are sufficiently robust and capable of efficient information transfer. Even though one would expect a wasp colony to be less complex because it has fewer individuals, a comparison demonstrates that there is a common design principle involved in different biological systems who have evolved to perform similar tasks

The paper was published in the journal Royal Society journal Interface during second week of October 2014.

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A potential therapeutic for septic shock

January 5, 2015

We sometimes hear of post-surgery infections, which can even result in untimely death. The life-saving surgery at times leads to a life threatening recovery. In the intensive care units of hospitals, microbial contamination induces massive inflammation leading to sepsis or septic shock. This has been a rising cause of mortality worldwide in the hospital intensive care unit admissions.

As the famous saying goes “the more the merrier” does not necessarily hold true with new drugs because “less is always more”. All we need is a single efficient drug to combat the sudden and rapid spread of sepsis in the intensive care units of hospitals.

Sepsis is caused by the uncontrolled expression of several inflammatory genes in the host, leading to irreparable damages. The sudden onset and excessive expression of these genes leads to accumulation of harmful metabolic end products, resulting in multiple organ failure. During such cellular stress, some proteins are activated. Development of inhibitors to these stress activated proteins can help devise treatment of such disorders.

The stress activated proteins are comprised of two main subsets- c-Jun N-terminal Kinase (JNK) and p38 Mitogen Activated Protein Kinase (MAPK). It is interesting to note that this work stems out of an extensive collaborative work by three groups from IISc, K. Durga Prasad and T. N. Guru Row from SSCU, J. Trinath and K. N. Balaji from MCBL and Anshuman Biswas and K. Sekar from Bioinformatics. Carefully planned chemical modifications on the commercially available and expensive JNK inhibitor SP600125 improve its ability to bind and inhibit JNK at very low concentrations. The inhibitor also reduces the expression of the inflammatory genes, which in turn cascade into septic shock.“Our study is among the first reports of the description and meticulous biochemical characterisation of selective JNK inhibitors” says Professor Balaji K. N.

This selective and more efficient inhibition activity of JNK inhibitors could facilitate the generation of novel therapeutics to treat sepsis and other inflammatory disorders. It can also pave the way to understand the essential biological function of signalling pathways related to JNK.

The paper appeared in the journal Scientific Reports in end November 2015.

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How your brain helps you see

February 2, 2015

You may worry that intelligent robots will replace humans any day, but that isn’t happening anytime soon. For now, the best computer algorithms cannot do even simple visual tasks like recognizing distorted letters. This is exploited each time we are asked to recognize distorted letters on website. These tests – called CAPTCHAS (for Completely Automated Public Turing test to tell Computers and Humans Apart) – are ubiquitous on the internet because they can prevent access to malicious computer programs. So what makes our brain so good at vision?

Through decades of research, neuroscientists have now found that there’s much more to vision than meets the eye. The eye works much like a camera. Light enters through the pupil and the lens focuses light onto a screen called the “retina”, which is akin to a camera film. Neurons leaving the retina carry information about the image to the visual areas in the brain, which occupy as much as 40% of the total real estate in the brain. This disproportionate area occupied by vision in the brain shows that vision is not easy for the brain either.

Dr SP Arun and his team have been studying biological vision at the Centre for Neuroscience, Indian Institute of Science, Bangalore. In a recent study, Arun and PhD student Ratan Murty have shed light on how the brain interprets the 2-dimensional image falling on the retina. “The image on the retina contains relevant as well as irrelevant information,” Arun says, “The same object can produce different images because of changes in lighting, size, position and three dimensional rotations. These irrelevant variations have to be factored out by the brain for it to understand that all these images belong to the same object. This computation is performed by neurons in the visual cortex.”

Ratan and Arun have performed recordings from the inferior temporal cortex of the monkey brain — an area that is known to be crucial for visual object recognition. They have found that flashing an image results in neural activity that builds up and drops over a period of time. During the build-up of the response, neurons are sensitive to irrelevant variations such as changes in the view point of an object. But in the later portion of the response, neurons respond to the same object ignoring irrelevant stimuli. “This transition from view dependence to view invariance has never been shown before, and it shows that neurons in this area perform this important computation dynamically over time”, said Ratan.

Ratan and Arun are performing a number of other experiments to understand how the brain processes three dimensional information. “Precisely how the brain ignores all the irrelevant variations is a fundamental problem in vision,” Ratan adds, “My experiments will help us understand at least the problem of viewpoint invariance better.” The researchers believe it is something that the brain has learned to solve over the course of evolution. Robots may beat us at algorithmic games like chess but they are nowhere near human competence in real-world tasks like vision.

The paper appeared online in the Journal of Neurophysiology during early 2015.

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A system to deliver drugs to individual cells

October 6, 2014

A system to package and deliver drugs to each cell of your body, depending on its needs, has been developed at IISc. “Nanocapsules” made from a special type of material can now deliver drugs right inside cancer affected cells in the body.

“Drug delivery systems” are mechanisms that can be programmed to release drug molecules at targeted cells in the body, using physiological cues present in the body itself. The major hurdle has been that these local cues are not consistent between cells; one needs systems that respond to multiple such cues. Prof. Ashok M Raichur and his team of scientists at the Indian Institute of Science, Bangalore, have demonstrated one of the very few systems that can respond to multiple cues.

There are three ideal characteristics that a drug delivery system should have: (1) the entire drug molecule should be encapsulated, which would prevent its premature release or degradation (2) it should carry the drug safely — and specifically — to the target site and (3) at the target site, it should release the drug molecules using the local physiological cues available.

Hollow nanocapsules were fabricated from special materials called biopolymers, which are materials that do not react with body tissues. These nanocapsules contain components that can respond to local cues integrated in the walls. To avoid premature release of the drug, the walls are crosslinked; this sort of architecture gives scope to load large amounts of drugs into the capsule. The wall structure also makes it possible for a small amount of local cues, like enzymes, to trigger the release of a large number of drug molecules.

The Food and Drug Administration(FDA) approved drug, polypeptide protamine (PRM), used to treat heparin induced toxicity, is one of the stimuli responsive components which is identified and actively cleaved into smaller fragments by trypsin like enzymes. The second component, chondroitin sulphate is susceptible to cleavage by enzyme hyaluronidase and has been used in the treatment of arthritis.

The Layer by Layer (LbL) assembly method used for fabrication of nanocapsules is carried under highly controlled mild conditions and thereby capable of incorporating the sensitive components (biopolymers) used here. It has the capacity to take up an array of materials ranging from small proteins to inorganic molecules. The nanocapsule surface was combined with a molecule used to identify cancer cells, folic acid (Vitamin B9, as we know it).

The drug delivery system was demonstrated using a population of cells in the lab – something called a “cell line”.

The paper appeared in the international journal RSC Advances on 17th September.!divAbs…

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Decoding transmembrane communication in living cells

April 24th, 2015

Living cells aren’t self-sufficient; they need to interact with their environment in order to survive. But these interactions are extensively controlled by the barrier called the cell membrane, a dynamic entity made up of lipids and proteins. Molecules are constantly passing in and out of the cell through the semi-permeable cell membrane, their movement often orchestrated by different forces and membrane components. This was the level of understanding of this barrier’s structure and function, posited by the ‘fluid mosaic’ model developed by Singer and Nicholson in 1972. Little was known then about minute details of the driving forces at the nano scale.

Until now, the nitty-gritty of how information traverses the membrane had been left to cell biologists’ countless hypotheses. Fast-forward to the 21st century, some of those assumptions have been put to rest by a recent study at NCBS. An interdisciplinary team has used living cells, synthetic lipid analogs and molecular dynamic simulations to understand transbilayer communication between molecules on either side of the bilayered cell membrane. The team consists of cell biologist Satyajit Mayor along with soft matter physicist Madan Rao and their teams at the National Centre for Biological Sciences, Bangalore, and synthetic chemists Ram Viswakarma (IIIM, Jammu) and Zhongwu Guo (Wayne State University, USA).

The team’s studies at the nanoscale have revealed that Phosphatidylserine (PS) is a key component that mediates the communication between the lipids on the inner leaflet, and actin and lipid-anchored proteins on the outer leaflet. PS gets the message across because of the presence of long chain-containing lipids such as those found in ‘solid fats’. That’s how the components on inner and outer leaflets communicate.  These studies show how integral PS is to signalling pathways of the cell, and therefore when absent results in irreparable damage.

“The uniqueness of the study lies in discovering a specific role for PS in nanocluster formation, a building block of ‘lipid rafts’ and how the chemistry of both the outer and inner leaflet facilitate this process. For this we have adopted an array of methods which combines biology, genetics, chemistry and physics to provide an explanation for the formation of nanoclusters” says Anupama Ambika Anilkumar, one of the first authors of the paper published online on 23 April, 2015, in the journal Cell.

Lipid rafts are microenvironments in the membrane made up of clusters of lipids and protein receptors, and are involved in molecule trafficking and assembly. Refuting early theories on the random combination of lipids to construct these lipid rafts, this study shows that the formation of these “nanoclusters” of lipids is an active process templated by the actin cytoskeleton on the inner leaflet. This understanding also points to further clues about the role of these clusters. They have been hypothesized to function as a ‘sorting station’ for components to be recruited for signalling events on the cell surface.

The discovery of PS as a vital component in the transmembrane communication would advance our understanding of the cell membrane’s microenvironment. It would also help scientists understand how these nanoclusters function and what proteins are involved in their assembly. Additional experiments in Mayor’s lab are underway to draw the complete picture of the cell’s communications and the anchors of the PS species. These entities also play an important role in various other cell functions and are hence important problems to pursue.

“There is no earlier evidence of how these clusters are formed by lipidic interactions. My colleague and co-first author, Riya Raghupathy established methods to assay the role of long-acyl chain lipid species, and along with Parvinder Pal Singh, developed the synthetic analogues used in this study. Anirban Polley, working with Madan, conducted molecular dynamic simulations; both of these are an integral part of this study and I am grateful for having such terrific collaborators,” said Anupama Anilkumar.

Decrypting this communication could help explain how signals are both read and interpreted by the cell, with implications for a number of diseases caused by alteration in lipid balance or composition. Understanding how these lipids, the “gatekeepers” of the cell, function might also help deter the progression of viral diseases, by potentially disrupting the interaction of membrane components with the viruses.

The paper can be accessed at:

Replacement with a single atom alters thyroid biochemical cascade in the body

June 8, 2015

More than 200 million people worldwide suffer from thyroid related disorders like hyperthyroidism, hypothyroidism, goitre, Hashimoto’s thyroiditis, thyroid cancer etc. Hyperthyroidism is also associated with various diseases like Grave’s disease, thyroid storm and toxic thyroid nodule. Most of these are treated with synthetic form of T4 for hypothyrodism and thiouracil-based drugs for hyperthyroidism. However, small variations in the drug concentration can lead to adverse effects.

Thyroxine or T4, having four iodine atoms is the thyroid pro-hormone, while the biologically more active metabolite tri-iodothyronine (T3) regulates body temperature, growth and heart rate. Thyroxine is produced by the thyroid gland and its metabolism is tightly regulated in human body. The activation or inactivation of thyroid hormones are mediated by enzymes in various cells/tissues. The activation occurs when T4 is converted to T3, but an inactivation occurs when T4 is converted to reverse T3 (rT3).

Earlier studies showed that simple chemical compounds containing sulfur or selenium atoms can remove iodine atoms selectively from T4 to produce rT3, thereby, mimicking the enzymes that mediate the inactivation pathway. For the first time, K Raja and Prof. G Mugesh from the department of Inorganic and Physical Chemistry, IISc, Bangalore, show that the replacement of sulfur or selenium by tellurium atoms dramatically alters the rate of the reaction. The compounds that mediated the conversion of T4 to rT3 can also mediate the conversion of T4 to T3 upon introduction of a tellurium atom. This study shows how a single atom change in a chemical compound can alter a very important biochemical reaction.

The team of scientists have developed a novel set of compounds that can mimic the function of the enzymes to activate or inactivate thyroxine (i.e. remove iodine atoms from T4 under physiologically relevant conditions). Prof. Mugesh said, “While the primary aim of this study is to understand the various mechanisms proposed for the model reactions as well as those catalysed by the natural deiodinases, the compounds developed are considered as potential candidates for the development of drugs for thyroid related disorders such as hyperthyroidism.”

The team aims to develop compounds that can control the thyroxine metabolism in the body rather than inhibiting the thyroxine biosynthesis or supplementing with thyroxine. Depending upon the nature of disease, a suitable enzyme mimic can be administered. The advantage of the current set of compounds is that they are highly reactive and the deiodination reactions can be performed in water at physiological conditions. The previous studies used organic solvents for the chemical transformations, and such conditions are not suitable for drug development. Though the current studies indicate that the compounds have potential applications in the treatment of hyperthyroidism, they need to be tested in human cell lines and animal models to understand the efficacy and toxicity.

The article appeared in the “Early View” section of Angewandte Chemie on 12th May 2015.

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