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  • We are pursuing a hit to lead

    2021-09-18

    We are pursuing a hit-to-lead medicinal chemistry campaign to optimize inhibitors of the HBV RNaseH. Here, we report the activity of seven new HIDs and nine new HPDs, with significant improvements in in vitro potency and cytotoxicity profiles for the HPD compounds.
    Materials and methods
    Results
    Discussion and summary We previously reported that 11 HIDs and a structurally related HPD inhibited HBV CU CPT 22 with low-to sub-micromolar efficacies, with TI values of 2.4–71 (Edwards et al., 2017). Therefore, we synthesized 16 new compounds, seven HIDs and nine HPDs, to examine the anti-HBV potential of these scaffolds.
    Summary We evaluated 16 novel compounds, seven HIDs and nine HPD compounds for activity against HBV replication in culture. Only three of the seven HIDs were active against HBV replication, and none of these compounds had a TI better than the best prior HID (#86, TI = 71). In comparison, synthesis of only nine new HPDs resulted in a more than 16-fold improvement in the TI over the best previous HPD (#208, TI = 22) (Edwards et al., 2017). We were able to achieve greater gains in potency and TI with the HPDs compared to the HIDs. Future efforts will focus on further improving the HPD scaffold with better TIs and improved selectivity over huRNaseH1, with the goal of developing a novel HBV RNaseH drug that can be used in combination with other inhibitors to provide better treatment to the millions of chronically infected patients.
    Competing intrests
    Acknowledgements
    Introduction Hepatitis B virus (HBV) infection and its associated liver diseases, such as cirrhosis and hepatocellular carcinoma, result in nearly one million deaths worldwide, annually according to World Health Organization estimates [1]. The disease disproportionately affects China, accounting for one-third of all HBV chronic carriers in the world with more than 90 million people affected. Current therapeutics for HBV rely on either nucleos(t)ide analogs (NAs) [2] or immunotherapy [3]. NAs such as lamivudine and entecavir effectively target the viral reverse transcriptase to suppress virus production, but do not decrease the formation of covalently closed circular DNA (cccDNA), which is responsible for viral persistence [4,5]. On the other hand, interferon therapy has only been effective in a small minority of patients and exhibits severe side effects [6]. There is clearly an on-going need for alternative therapeutic targets to increase cure rates and decrease the global threat posed by HBV, despite the availability of vaccines to manage this disease. This review provides a summary of recent advances in the development of small molecule capsid assembly modulators (CAMs) and the progress achieved in understanding their interactions with HBV core proteins, with a particular emphasis on articles published in the past three years.
    Capsid assembly modulators In recent years, significant attention has been paid to the discovery and development of CAMs, which generally fall within one of five main classes: phenylpropenamides (PPAs), heteroaryldihydropyrimidines (HAPs), sulfamoylbenzamides (SBAs), sulfamoylpyrroloamides (SPAs), and glyoxamoylpyrroloxamides (GLPs) (Figure 1). CAMs allow exposure of cccDNA to degrading enzymes, preventing cccDNA formation during de novo infection [] and are hypothesized to have a higher barrier to drug resistance than NAs [11]. CAMs also recently demonstrated the ability to cause capsid disassembly []. Thus, this approach should be beneficial both for the development of novel antivirals and for combination therapy with NAs so that multiple mechanisms are targeted simultaneously to perhaps induce synergy
    Summary and future directions Current HBV therapeutics suppress viral replication but are ineffective as a cure for the disease as they do not eradicate cccDNA, which provides for viral persistence. This review highlights recent advances in the development of CAMs to suppress HBV viral load and decrease cccDNA formation. As studied in various cell lines SPAs and GLPs demonstrate promising in vitro and in vivo activities, but more focus on efficacy and safety results is warranted. Examining the utility of new molecules is limited to clinical trials as there is a lack of cell cultures that support multiple rounds of HBV infection, and are limited in the study of viral spread. Furthermore, all of the cell cultures produce extremely low quantities of cccDNA which is another limitation that needs to be addressed in the future [45]. However, with the emergence of novel CDMS studies of the nucleocapsid assembly process, experiments using CAMs could highlight whether these modulators interfere with the actual assembly or with the self-correction process of nucleocapsids. Furthermore, the application of CAMs in combination with existing antiviral agents could identify a tandem CU CPT 22 mechanism to block cccDNA formation to achieve a clinical cure.