Virus cracking molecules for treating Hepatitis B

Indiana University researchers have made an important step forward in the design of drugs that fight the hepatitis B virus, which can cause liver failure and liver cancer. ''The drug could attack hepatitis B virus on multiple fronts-preventing replication and killing new copies of the virus," said senior author Adam Zlotnick, a professor in the IU Bloomington College of Arts and Sciences' Department of Molecular and Cellular Biochemistry.

A virus reproduces by hijacking a host's cellular machinery to produce more of the virus. The majority of viruses protect their genetic material-DNA or RNA-inside a protein shell called a "capsid." The research leads to discovery of  a class of molecules called core protein allosteric modulators, or CpAMs, that disrupt capsid protein assembly.

CpAM molecules attack viruses by causing their shells to assemble incorrectly, interrupting the life cycle of the virus. Previously, CpAMs were seen as only able to disrupt a virus during formation of the capsid, after which its DNA was protected inside a hard casing.

To make their discovery,  researchers bound the CpAM to a chemical called TAMRA-a crimson-colored dye used in some red lipstick-to make it fluorescent and easier to detect in experiments. Using cryo-electron microscopy, they found the small CpAM molecule could make the large, soccer ball-shaped virus capsid bend and distort.

The big implication is viral capsids aren't as impenetrable,  if this type of interference works against hepatitis B virus, it might also work against other viruses. About half of known virus families have soccer ball-like capsids; examples include polio and herpes.  This study may lead to better treatments against them since the mechanisms behind capsid disruption could lead to drugs against any of them.
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Three-dimensional organization of DNA

The three-dimensional organization of DNA in the nucleus influences our biology, from how our genome organized our cellular activity to how genes are passed from parents to children.

 X-rays and microscopy showed that the primary level of chromatin organization involves 147 bases of DNA spooling around proteins to form particles approximately 11 nanometers (nm) in diameter called nucleosomes.

These nucleosome "beads on a string" are then thought to fold into discrete fibers of increasing diameter (30, 120, 320 nm etc.), until they form chromosomes.

Researchers used ChromEMT to image and measure chromatin in resting human cells and during cell division (mitosis) when DNA is compacted into its most dense form -the 23 pairs of mitotic chromosomes that are the iconic image of the human genome.

Chromatin that has been extracted from the nucleus and subjected to processing in vitro - in test tubes - may not look like chromatin in an intact cell, so it is tremendously important to be able to see it in vivo.

Chromatin's packing density, and not some higher-order structure, that determines which areas of the genome are active and which are suppressed.

Controlling access to chromatin could be a useful approach to preventing, diagnosing and treating diseases like cancer.

Chromatin does not need to form discrete higher-order structures to fit in the nucleus, It's the packing density that could change and limit the accessibility of chromatin, providing a local and global structural basis through which different combinations of DNA sequences, nucleosome variations and modifications could be integrated in the nucleus to exquisitely fine-tune the functional activity and accessibility of our genomes.
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