Discovery and development of NS5A inhibitors
This kinase takes part in the biosynthesis of phosphatidylinositol 4-phosphate (PI4P) by interacting with NS5A, which stimulates its activity and appears to improve the integrity of the membranous web.
These inhibitors have achieved a significant reduction in HCV RNA blood levels and can therefore be considered as potent antivirals.
[2][30] Most studies assume that NS5A inhibitors act on two essential stages of the HCV life cycle; the replication of the genomic RNA, and virion assembly.
[31] Even though the mechanism is not completely understood, it has been demonstrated that the inhibitors downregulate NS5A hyperphosphorylation, leading to the suppression of HCV replication and its processing of polyproteins, as well as resulting in an unusual protein location.
[34] NS5A inhibitors appear to furthermore disrupt the formation of new replicase complexes resulting in a gradual slowing of viral RNA synthesis.
[40][41][42] The ever present risk of viral strains developing resistance has been a main factor in why they are used in combination with one or more complementary drug.
[43] Adverse effects, and extensive and complicated drug regimens with accompanying low compliance rates, have been a hindrance in the development of antiviral treatments.
NS5A is among the seven nonstructural proteins that form a complex with viral RNA within infected cells to initiate HCV replication.
[46] The development of antiviral drugs capable of interfering with the proteins responsible for viral replication has been intimately linked with advancements in techniques for establishing the efficient cell culture systems needed to screen for them.
[46] In 1999 a breakthrough came when a full-length consensus genome cloned from HCV RNA was found to replicate at high levels when transfected into a human hepatoma cell line.
The first in this new class of drugs was daclatasvir (Daklinza), gaining first global approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) in July 2014 in combination with asunaprevir.
[53] This has shaped the focus of NS5A inhibitor development, from which asymmetrical variants that metabolize into analogues with complementary resistance profiles have emerged, amongst other discoveries.
[5] The natural L-configuration of the proline derivatives was found to be critical for inhibition since the unnatural D-configuration had drastically weaker activity.
[55] Favorable characteristics in an NS5A inhibitor include high potency and long plasma half-life in order to achieve a once-daily-dosage.
[6] Among the HCV quasispecies there are pre-existing variants with the potential to confer resistance to NS5A inhibitors without having any previous exposure to those drugs.
This pattern is often associated with amino acid substitutions that confer upon the virus a robust drug resistance without impairing the viral fitness.
Therapeutic gaps for individuals with complicating conditioned such as chronic kidney disease and cirrhosis will need to be bridged.
Shorter therapies with milder side effects would yield greater adherence, and the ever present spectre of drug resistance is looming.
The highly adaptive HCV has evolved into a number of different genomes that all need to be adequately treated, preferably with pan-genotypic regimens.
[42][59] In vitro, ABT-530 showed potency against the resistance associated variants which are immune to the first generations of NS5A inhibitors, including ledipasvir, daclatasvir and ombitasvir.
[42] Because this drug combination has the additional quality of being hepatically cleared, it holds the promise that patients with chronic kidney disease and HCV could receive a safe, non-sofosbuvir-based treatment in the near future.
