Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • hmg-coa reductase Different SVR rates have been observed whe

    2021-11-29

    Different SVR rates have been observed when comparing GT 1a- and 1b-infected patients receiving BOC or TLP therapy. The response rates in patients infected with GT 1b have generally been more favourable than in those with GT 1a [26]. In our study, persistence mutations were only observed in HCV GT 1a-infected patients. This is partially due to the lower genetic barrier of GT 1a versus 1b [14], [27]. It would be interesting to study the distribution of frequency of the detected intra-host variants.
    Funding
    Conflict of interest
    Ethical approval
    Author’s contributions
    Acknowledgment
    Hepatitis C virus (HCV) is a major cause of chronic liver disease that can lead to cirrhosis, carcinoma and liver failure. It is estimated that over 200 million people are chronically infected with this virus and it is the leading cause of liver transplants. The current standard treatment for HCV infection is based on a combination therapy of injectable pegylated interferon-α (PEG IFN-α) and antiviral drug ribavirin. This treatment, indirectly targeting the virus, is associated with significant side effects often leading to treatment discontinuation in certain patient populations. In addition, approximately 50% of genotype-1 (the predominant genotype in the US) patients do not respond to this treatment regimen. Giving the high prevalence of the disease infection worldwide, there is an enormous unmet medical need for new therapies against HCV infection. HCV NS3/4A protease inhibitors have emerged as a promising potential treatment for HCV infection. Two major classes of NS3 protease inhibitors have been developed. The first class is comprised of serine-trap inhibitors. The most advanced drugs are VX-950 (telaprevir) and SCH-503034 (boceprevir), currently in Phase III clinical trials. The second class is represented by reversible noncovalent inhibitors such as BILN-2061 (ciluprevir, ), the first compound in its class to achieve clinical proof of concept. Although its development was halted due to cardiac issues in animals BILN-2061 prompted extensive investigation on further optimization of the peptide framework and P1 carboxylic hmg-coa reductase region. To replace the P1 carboxylic acid, many different groups (e.g., tetrazole, acylcyanamide, acysulfonamide, phosphonate) have been studied. Among them, cyclopropyl acylsulfonamide appears to be the preferred replacement for the P1 carboxylic acid. Further application of this strategy led to the discovery of a number of clinical candidates including ITMN-191 (danoprevir), TMC-435350 (medivir) and MK-7009 (vaniprevir), currently in advanced clinical trials. However, rapid emergence of drug-resistance has recently been observed for HCV NS3 protease inhibitors. Therefore, there remains a need for the discovery of new HCV NS3 protease inhibitors with novel binding properties. As part of our continued efforts to discover novel HCV NS3 protease inhibitors, we envisioned that acylsulfamoyl benzoxaborole could be used to replace the cyclopropyl acylsulfonamide moiety (). Benzoxaboroles, are organoboron compounds that have emerged as a new class of potential therapeutic agents. Compounds containing a benzoxaborole moiety have been shown to interact with a variety of biological targets and also exhibit good drug properties. Studies of a hypothetical benzoxaborole inhibitor derived from danoprevir (ITMN-191) docked into HCV NS3 protease suggest the benzoxaborole moiety can potentially form polar interactions with Thr 42, and positively charged Lys 136 (). Our strategy was to scan for new potential benzoxaborole interactions with the protease by exploring the impact of two distinct macrocyclic series and different regioisomers of acylsulfamoyl benzoxaboroles on the inhibitory potency. Boronate or , an important intermediate towards the 6-acylsulfamoyl benzoxaboroles, was prepared according to . Reaction of bromide with pinacol diborane in the presence of palladium catalyst afforded boronate . Bromination of with NBS and AIBN gave benzyl bromide . Subsequently, treatment of with sodium acetate in glacial acetic acid gave the corresponding benzyl acetate . Reaction of with sodium hydroxide followed by acid treatment resulted in 6-sulfamoyl benzoxaborole . We found that either boronate or could be coupled to HCV NS3 inhibitor scaffolds to form the targeted acylsulfamoyl benzoxaborole inhibitors.