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Unravelling the mechanism of allosteric hepatitis C virus inhibition – a new HOT article

New insights into how the spread of hepatitis C virus (HCV) can be prevented using an enzyme inhibitor have been reported in Molecular BioSystems.

Free and bound protein

Motion modes of the free and bound protein from PCA analysis

Hai-Feng Chen’s group at Shanghai Jiaotong University used molecular dynamics to study the effect of a cyclopropylindolobenzazepine derivative, M2. The technique was used to model just how M2 suppressed a key viral protein, NS5B, to stop the virus from replicating.

M2 is known to be an efficient and highly specific HCV inhibitor. Because the enzyme it targets has no mammalian equivalent, it could be used to fight viral infection without any risk of it adversely affecting any important human enzymes. However, exactly how its inhibition works isn’t yet known.

The group found that when M2 bound to NS5B it caused a conformational change through an allosteric mechanism, changing it from an “open” to a “closed” form. This change destabilised the enzyme, altering information transfer from the substrate binding site to the catalytic domain and drastically weakening its effect. The M2-bound enzyme had greater structural variation – particularly in its A1 loop – indicating its lack of stability.

The allosteric mechanism was confirmed by testing a weakened form of M2, which had significantly less effect on the connectivity of the enzyme than the normal version. A further in vitro resistance study reinforced this by comparing the normal enzyme to a mutant version with a truncated A1 loop. Inhibition of the mutant version was far less effective than that of the wild type, highlighting the importance of the A1 loop in the inhibition mechanism.

Understanding exactly how M2 inhibits viral NS5B, and how mutated forms of the virus might resist this, is vital – it could in future lead to new and more effective drugs to fight HCV.

Read the full article here:

Allosteric mechanism of cyclopropylindolobenzazepine inhibitors for HCV NS5B RdRp via dynamic correlation network analysis
Mueed ur Rahman, Hao Liu, Abdul Wadood and Hai-Feng Chen
Mol. BioSyst., 2016, Advance Article
DOI: 10.1039/C6MB00521G

Susannah May is a guest web writer for the RSC Journal blogs. She currently works in the Publishing Department of the Royal Society of Chemistry, and has a keen interest in biology and biomedicine, and the frontiers of    their intersection with chemistry. She can be found on Twitter using @SusannahCIMay.

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