Cryo electron microscopy next big thing in drug target discovery

Cryo- electron microscopy is a form of transmission electron microscopy where sample is analyzed at cryogenic temperature, this technique enable researcher to visualize potential drug target sites on proteins/enzymes with higher resolution in contrast to X-ray crystallography which require crystallization of specimen and however not all proteins can be crystallized easily, and those that do crystallize may not display the same shape that is present in their natural environment, either since the protein shape can be modified by crystallization additives or by the contacts that form between neighboring proteins within the crystal lattice.

Cancer cells require continuous nutrients supply  which they maintain by altering activation rate of key metabolic enzymes like mitochondrial enzymes pyruvate carboxylase and glutaminase, the expression of these enzymes increases several folds in lung cancer patients. Hence targeting metabolic enzymes is another form of cancer treatment but success story relies on clear idea about potential target sites on these enzymes for drugs to act on and CRYO-EM can be answer to this problem

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Improved resolution of atomic details of proteins from left to right by advances in cryo-EM technology 

Researchers  were able to capture images of glutamate dehydrogenase, an enzyme found in cells, at a resolution of 1.8 angstroms, a level of detail at which the structure of the central parts of the enzyme could be visualized in atomic detail. The scientists from the National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues also reported achieving another major milestone, by showing that the shapes of cancer target proteins too small to be considered within the reach of current cryo-EM capabilities can now be determined at high resolution.Two of the small proteins the researchers imaged in this new study, isocitrate dehydrogenase (IDH1) and lactate dehydrogenase (LDH), are active targets for cancer drug development. Mutations in the genes that code for these proteins are common in several types of cancer. Thus, imaging the surfaces of these proteins in detail can help scientists identify molecules that will bind to them and aid in turning the protein activity off.

 

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Targeted Photoimmunotherapy : Promising approach for cancer treatment..

  • Tumour micro environment has both T cells which can destroy cancer and TREGS regulatory T cells. TREGS suppress the immune response in tumour microenvironment which results in unchecked proliferation of cancerous cells.
  • Targeted photoimmunotherapy selectively target TREGS so that T cells can check cancer growth.
  • In near infrared photoimmunotherapy (NIR-PIT) photoabsorber is conjugated to antibody that selectively binds to cell surface receptor of cancer cells.When in mice model for cancer conjugated antibodies are injected these conjugated antibodies binds with receptors on their target cells (TREGS).
  • After binding with target cells infrared illumination is given to mice ( Experimental mice had healthy immune system but with tumour made up of mice lung or colon cancer cells and then implanted under their skin ) leading to activation of conjugated antibody resulting in selected swelling and bursting of TREG. Due to bursting TREG releases their content in surrounding tumour microenvironment which leads to activation of T cells.13095985_922172651215162_5152497112618807080_n.jpg