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Archive - Jul 10, 2019

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Newly Identified Protein (KHNYN) Works with ZAP Protein to Promote Destruction of HIV Virus Containing Clustered CpG Dinucleotides

A newly identified protein called KHNYN teams up with ZAP (image), a known virus-killing protein, to destroy viruses related to HIV. KHNYN has been identified as a missing piece in a natural antiviral system that kills viruses by targeting a specific pattern in viral genomes, according to new findings published online on July 9, 2019 in eLife. The open-access article is titled “KHNYN Is Essential for the Zinc Finger Antiviral Protein (ZAP) to Restrict HIV-1 Containing Clustered CpG Dinucleotides.” Studying the body's natural defenses to viruses and how viruses evolve to evade them is crucial to developing new vaccines, drugs, and anticancer treatments. The genetic information that makes up the genomes for many viruses is comprised of building blocks called RNA nucleotides. Recently, it was discovered that a protein called ZAP binds to a specific sequence of RNA nucleotides: a cytosine followed by a guanosine, or CpG for short. The human immunodeficiency virus (HIV) normally escapes being inhibited by ZAP because it has evolved to have few CpGs in its genome. However, when CpGs are added back to the virus, ZAP promotes its destruction. This helps us understand why HIV with more CpGs multiplies less successfully, and likely explains why many strains of HIV have evolved to have few CpGs. But a mystery remained because ZAP is unable to break down the viral RNA by itself. "As ZAP can't degrade RNA on its own, we believed that it must recruit other proteins to the viral RNA to destroy it," says lead author Mattia Ficarelli, a PhD student in Dr. Chad Swanson's Lab, Department of Infectious Diseases, King's College London.

Two Potentiator Drugs Act on CFTR Protein in Cystic Fibrosis by Holding Hinge Open to Allow Ion Flow; Focus on This Mechanism May Enable Further Progress on Drug Development & Disease Treatment

In recent decades, treatment options for people with cystic fibrosis have improved dramatically. The newest drugs, known as potentiators, target a protein called cystic fibrosis transmembrane conductance regulator (image), which is mutated in people with the disease. Yet, while these medications can help some people with CF, they are far from perfect. Moreover, researchers haven't been able to figure out how the drugs actually work--until now. A new study by Rockefeller University scientists in New York characterizes, for the first time, the interaction between potentiators and the protein they target at atomic resolution. The research, described in a report in the June 21, 2019 issue of Science, shows that two distinct compounds act on the same protein region--a finding that points to strategies for developing more effective drugs. The article is titled “Structural Identification of a Hotspot on CFTR for Potentiation.” The cystic fibrosis transmembrane conductance regulator (CFTR) is a channel that, when open, allows chloride ions to move in and out of cells. When CFTR is mutated, ions cannot flow freely, leading to changes in the make-up of mucus lining internal organs. These changes can be particularly dangerous in the lungs where they cause thick mucus to accumulate, often leading to impaired breathing and persistent infections. Potentiators are used to increase the flow of ions through CFTR, ameliorating some symptoms of cystic fibrosis (CF). Currently, only one such drug, known as ivacaftor, is on the market; another, called GLPG1837, is now in development. "Ivacaftor can improve lung function by about ten percent. It can help a lot, but it's not a cure and not everybody responds to it," says Jue Chen, PhD, the William E. Ford Professor at Rockfeller.