Hépato-Gastro & Oncologie Digestive


Anti-NS5A: mechanism of action, pharmacology and virological characteristics Volume 23, supplement 1, Février 2016


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1 CHU de Grenoble,
Institut de Biologie et Pathologie,
Laboratoire de Virologie,
38043 Grenoble cedex 9,
2 Université Grenoble Alpes,
F-38000 Grenoble,
F-38000 Grenoble,
* Tirés à parts

Even though NS5A has no known enzymatic activity, its multiple roles in hepatitis C virus replication and particularly its interaction with the membranous web which has a critical role in the replication complex of hepatitis C virus suggests NS5A as an attractive target for direct antiviral inhibition of the infection. Anti-NS5A compounds isolated by high throughput screening on HCV replicon systems exhibits high potency and a broad activity accross genotypes. NS5A-inhibitors are now part of IFN-free regimens for the treatment of hepatitis C infection in combination with viral polymerase inhibitors and/or viral protease inhibitors. Their pharmacokinetic properties allow them to be administered once a day. Because of a low genetic barrier to resistance of these drugs, HCV variants with decreased susceptibility can emerge and compromise therapy. Resistance associated variants (RAVs) have been mapped to the N-terminal region of HCV NS5A (within the first 100 amino acids). Their investigation is complicated by the variability of the genetic region to sequence and the interpretation depending on the viral genotype. The frequency of baseline resistance associated polymorphisms varies among genotypes but is still not clearly related to sustained virological response when using combined therapies. RAVs seems to persist long time and should be investigated before a second line therapy. A second generation of anti-NS5A compounds is currently undergoing clinical trials. They exhibit a wider pangenotypic activity and a better sensitivity to RAVs.