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George Chandy

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Professor George Chandy
MBBS, PhD
Professor of Molecular Physiology
Principal Investigator, Molecular Physiology Laboratory​
Email: gchandy@ntu.edu.sg

 

 
Team
 
  • Dr Bajaj Saumya, Research Fellow
  • Han Jingyao, Research Assistant
  • Ng Xuan Rui, Research Assistant


Introduction

Professor George Chandy graduated from Christian Medical College (CMC) Vellore, one of the premier medical schools in India. After graduation, he joined a Virology laboratory at CMC which piqued his interest in research. He then pursed his PhD at the University of Birmingham, Department of Immunology. In 1983, he moved to the University of California Irvine ( UC Irvine) as a postdoctoral clinician-scientist researcher in the Division of Basic and Clinical Immunology, Department of Medicine, where he did clinical work in the Division’s Clinic while pursuing research under the laboratory of the Division Chief, Professor Sudhir Gupta. He moved to the Department of Physiology and Biophysics at UC Irvine in 1990 and was eventually promoted to Professor.

Prof Chandy is an elected member in the Henry Kunkei Society and has been awarded the Athalie Clarke Award: Excellence in Research. His papers have been published in peer-reviewed journals such as Nature, Science and Journal of Clinical Investigation. He has also been listed in Thomson Reuters’s report on World Most Influential Scientific Minds 2014 as one of the Highly Cited Researchers.

Prof Chandy is currently a Professor of Molecular Physiology at Lee Kong Chian School of Medicine, NTU.


Research Focus

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Between academic research and the completion of human phase-1 safety trials (when drugs are often licensed by biopharmaceutical companies) lies a “valley of death”, where promising discoveries frequently stall. Prof Chandy and his team aim is to bridge this valley of death. To achieve this goal, they are building a Translational Research Program focused on potassium channel-targeted therapeutics for autoimmune, fibrovascular and infectious diseases.

Potassium Channels
Potassium channels are the largest family of ion channels, with 76 genes in humans. The diversity of potassium channels in different physiological systems, coupled with their important functional roles, makes them excellent targets for selective modulation of specific tissues and functions. Prof. Chandy’s group focuses on potassium channels as therapeutic targets. 

The Kv1.3 Channel: Therapeutic target for Autoimmune Diseases
Commonly used immunosuppressant drugs cause side effects because they broadly suppress the immune system. A subset of T lymphocytes called effector memory T cells (TEM cells) play a critical role in the development of autoimmune diseases. Therapeutics that selectively silence TEM cells without compromising protective immune responses by other T lymphocytes would have significant advantages over existing drugs. Prof. Chandy and his collaborators identified and cloned the Kv1.3 channel, demonstrated its role in TEM cells, and developed selective inhibitors of the channel, one of which (ShK-186 / Dalazatide) has progressed to human trials and shown efficacy in patients with plaque psoriasis (Fig. 1). His team is now focused on a novel class of Kv1.3 inhibitors they discovered in food. These peptides are potent, selective, extremely stable and effective in animal models of autoimmune diseases. Prof. Chandy’s group hopes to advance these inhibitors to human trials (Fig. 1). Prof. Chandy’s group is also determining the atomic structure of Kv1.3 bound to specific inhibitors. Such structural information on drug-binding pockets will guide design of next-generation therapeutics.

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The KCa3.1 Channel: Therapeutic target for Fibrosis
The KCa3.1 potassium channel has been extensively validated as a therapeutic target for fibrosis. Pharmacological blockade of this channel by selective inhibitors or knockout of the KCa3.1 channel gene, ameliorates renal, liver, lung and cardiac fibrosis in rodent and sheep models. Prof. Chandy’s group has two ongoing campaigns to develop orally bioavailable and safe specific inhibitors of the KCa3.1 channel for use as therapeutics for renal (due to diabetes) and liver (due to fatty liver disease) fibrosis. The first drug discovery campaign is with scientists at Experimental Therapeutics Center, A*STAR, and the second is with chemists at NTU and molecular modelers at the BioInformatics Institute, A*STAR (Fig. 2).  They are also determining the atomic structure of KCa3.1 bound to specific inhibitors.

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Potassium Channels in pathogenic bacteria as therapeutic targets for new antibiotics
The resistance of pathogenic bacteria to antibiotics is an increasingly serious threat to global public health that requires action across all government sectors and society. Recent studies suggest that bacteria living in communities (biofilms) communicate with each other through electrical signals transmitted by potassium. Disruption of this signalling disrupts the bacterial biofilm. Prof. Chandy’s group is studying the network of potassium channels and transporters in Mycobacterium tuberculosis (the cause of TB) and in Pseudomonas aeruginosa (Gram negative bacterium that causes severe infections) to identify those that can be targeted by drugs for next generation antibiotics (Fig. 3). 

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Selected Publications

DeCoursey TE, Chandy KG, Gupta S, et al. (1984). Voltage gated potassium channels in human T lymphocytes: A role in mitogenesis? Nature. 307:465.

Chandy KG, DeCoursey TE, Cahalan MD, et al. (1984). Voltage-gated potassium channels are required for human T cell activation. The Journal of Experimental Medicine. 160:369.

Grissmer S, Dethlefs B, ... Chandy KG. (1990). Expression and chromosomal localization of a lymphocyte K+ channel.  Proceedings of the National Academy of Sciences. 87:9411.

Wulff H, Miller M, ... Chandy KG. (2000). Design of a selective inhibitor of the intermediate-conductance calcium-activated K+ channel, IKCa1: A potential immunosuppressant. Proceedings of the National Academy of Sciences. 78:8151.

Wulff H, Calabresi P, ... Chandy KG. (2003). The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. The Journal of Clinical Investigation, 111:1703.

Beeton C, Wulff H, ... Chandy KG. (2006). Kv1.3 channels: Therapeutic target for T cell-mediated autoimmune diseases. Proceedings of the National Academy of Sciences, 103:17414.

Upadhyay SK, Eckel-Mahan K, ... Chandy KG. (2013). Selective Kv1.3 blocker as therapeutic for obesity and insulin resistance. Proceedings of the National Academy of Sciences, 110:E2239-48.

Chandy KG, & Norton RS. (2016). Immunology: Channeling potassium to fight cancer. Nature 537:497-499.
 
Chandy KG, & Norton RS. (2017). Peptide blockers of Kv1.3 channels in T cells as therapeutics for autoimmune disease. Current Opinion in Chemical Biology. 38:97-107.

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